Emerging bioactive microneedle platforms for disease management: From cutaneous disorders to systemic therapeutics

Abstract

Beyond their conventional role as passive transdermal delivery vehicles, microneedle (MN) platforms now function as active bio-interfaces capable of modulating therapeutic responses in both localized and systemic diseases. This review summarizes recent advances in MN technology, focusing on the transition from traditional matrix-controlled delivery to bioactive microneedles. Although localized applications at barrier surfaces, such as treating cutaneous disorders and mucosal lesions, remain a fundamental focus, this review emphasizes the application of MNs in complex chronic metabolic diseases (e.g., diabetes), oncology (e.g., melanoma and glioblastoma), and deep-tissue degenerative diseases of the cardiovascular, nervous, and musculoskeletal systems. Integrating stimuli-responsive materials, including metal-organic frameworks (MOFs), aggregation-induced emission luminogens (AIEgens), and smart hydrogels, with external physical stimuli enables autonomous, closed-loop interventions, thereby advancing personalized systemic therapy. Furthermore, we summarize recent progress in applying MNs to non-traditional sites and deep-tissue repair. Finally, rather than focusing solely on phenotypic efficacy, we discuss key translational challenges, including manufacturing scalability, biosafety, and regulatory pathways, to guide future clinical translation.

Graphical abstract

Schematic overview of bioactive microneedle (MN) platforms for disease management. The diagram illustrates the structural design and therapeutic applications of MN systems, depicting their evolution from local/barrier-surface therapy to systemic/deep-organ intervention. Three core dimensions are integrated: advanced materials, stimuli-responsive mechanisms, and therapeutic cargo delivery.• Architectural Diversity: The central panel highlights diverse structural configurations—including dissolving, multilayer, barbed, thread-structured, core-shell, and porous/perforated designs—engineered to facilitate either localized barrier-surface penetration or systemic, deep-organ therapeutic delivery.• Bio-responsive Material Logic: The integration of advanced bioactive materials (e.g., MOFs, AIEgens, and stimuli-responsive hydrogels) with internal or external triggers (e.g., pH, ROS, NIR light, ultrasound, and electricity) enables high-fidelity, spatiotemporal control over drug release kinetics.• Therapeutic Paradigm Shift: The platform supports a comprehensive range of clinical applications, moving from local/barrier-surface therapies for cutaneous inflammation, scars, and chronic wounds to autonomous, systemic/deep-organ interventions for chronic metabolic disorders, complex malignancies, and cardiovascular, neurological, and musculoskeletal pathologies.• Bioactive Cargoes: MN arrays function as engineered carriers for complex therapeutic payloads, including small molecules, biologics, exosomes, gene modulators, and living cells, to achieve active microenvironment modulation and regenerative orchestration.

Highlights

• •Microneedles evolved from passive delivery to autonomous “sense and treat” bio-interfaces.
• •Platforms enable systemic and deep-organ therapies for chronic and malignant diseases.
• •Stimuli-responsive materials provide high-precision control over drug release kinetics.
• •Closed-loop systems facilitate personalized treatment for metabolic and oncological cases.
• •Bio-hybrid systems and robotic interfaces define the frontier of regenerative healthcare.

1. Introduction

The integration of biomedical engineering and nanotechnology has established microneedle (MN) technology as a promising platform for transdermal therapy [1,2], providing a minimally invasive alternative to conventional oral and parenteral administration [3]. By utilizing micron-scale projections to penetrate the stratum corneum (SC), MN arrays create transient aqueous microchannels that facilitate the efficient delivery of diverse therapeutic agents, from small molecules to complex cellular payloads [[4], [5], [6]]. This localized disruption of the cutaneous barrier optimizes bioavailability and improves patient compliance by reducing the systemic side effects and procedural pain associated with traditional administration methods [7].

Conventional administration strategies, particularly oral dosing and hypodermic injections, are often limited by clinical challenges such as first-pass hepatic metabolism, gastrointestinal degradation, and patient anxiety regarding needles. MN-mediated delivery circumvents these limitations by depositing therapeutics directly into the viable epidermis or dermis [8]. This direct access to the dermal vascular and lymphatic networks ensures rapid or sustained absorption while minimizing infection risks and pain, making MNs highly suitable for both acute interventions and chronic disease management.

The functional versatility of MNs stems from their structural diversity, which includes solid, coated, hollow, porous, dissolving, and hydrogel-forming types. Solid MNs, fabricated from medical-grade metals or high-strength polymers, utilize a “poke-and-patch” approach to mechanically disrupt the SC [[9], [10], [11], [12]]. Conversely, hollow and porous architectures integrate microfluidic principles for the controlled infusion of macromolecular biologics, such as monoclonal antibodies and nucleic acid vaccines [[13], [14], [15], [16], [17]]. For applications requiring programmed release, dissolving MNs employ biocompatible matrices that encapsulate payloads and release them via in situ degradation [18,19]. Similarly, hydrogel-forming MNs absorb interstitial fluid (ISF) to form a swelling-triggered diffusive reservoir for prolonged drug delivery [[20], [21], [22], [23], [24]].

Beyond functioning as simple physical penetration enhancers, MNs are evolving into bio-interactive platforms for regenerative medicine. By bypassing the physical barrier of the SC, they improve the efficacy of topical treatments for refractory skin conditions and chronic non-healing wounds, which are typically characterized by therapeutic resistance [25,26]. In this review, “bioactive microneedles” are defined as platforms where the constituent materials or incorporated cargoes actively participate in biological modulation beyond passive drug release. This includes stimuli-responsive degradation, enzymatic activity, reactive oxygen species (ROS) scavenging, immunomodulation, and in situ biosynthesis. This review summarizes recent developments in MN-based therapeutics, examining their dual role as physical penetration enhancers and engineered bioactive carriers. The discussion focuses on the utility of MNs in modulating the local tissue microenvironment in various pathologies, such as hypertrophic scars, acne vulgaris, and diabetic foot ulcers [27].

Beyond localized cutaneous applications, MN technology has expanded significantly toward systemic disease management and deep-tissue intervention. Recent advances in this area follow three converging directions: (i) the development of mechanically robust, bioresorbable MN architectures capable of penetrating non-cutaneous barriers, such as the oral mucosa, corneal epithelium, and annulus fibrosus [28,29]; (ii) the use of stimuli-responsive materials to enable autonomous, lesion-specific drug release in pathological microenvironments distant from the administration site [30]; and (iii) the integration of external energy modalities (e.g., near-infrared (NIR) light, ultrasound, electric fields) and biosensing capabilities to facilitate closed-loop therapeutic modulation of deep organs, including the myocardium, intervertebral discs, and central nervous system. Representative applications include MN-mediated cardiac gene therapy via epicardial delivery [29], intradiscal exosome release for intervertebral disc regeneration [28], and nose-to-brain drug transport that bypasses the blood-brain barrier [30]. This transition from barrier-surface modulation to systemic and deep-organ intervention requires the re-evaluation of MN mechanical properties, biostability, and energy-coupling strategies, forming the core organizational framework of this review.

The rapid expansion of MN applications has prompted numerous comprehensive reviews. Early foundational works established the pharmacological rationale for transdermal MN delivery [1] and systematically classified structural variants (solid, hollow, dissolving, and hydrogel-forming) along with their fabrication methodologies [9,16,17]. Disease-centric reviews have cataloged MN interventions in dermatology [25,26], oncology [[31], [32], [33], [34], [35], [36]], and diabetes [[37], [38], [39], [40], [41], [42]], but typically treat each indication as an isolated domain. More recently, stimuli-responsive MN systems have been reviewed from a materials science perspective [43], emphasizing smart hydrogels, metal-organic frameworks (MOFs), and nanozymes, but lacking a systematic linkage to pathological microenvironmental cues. Additionally, a comprehensive review outlined a clinical translation roadmap for anti-psoriatic MN technologies, highlighting manufacturing scalability and regulatory consensus as critical benchmarks [44]. However, a systematic framework bridging stimuli-responsive material design with organ-specific pathological microenvironments across the full spatial spectrum, from barrier surfaces to deep organs, remains underdeveloped. The present review addresses this gap by advancing three interconnected analytical perspectives: (1) microenvironment-responsive engineering logic, (2) spatial-therapeutic expansion, and (3) critical translational assessment.

To facilitate cross-study comparisons, pathology-specific tables summarize material parameters, release kinetics, animal models, and therapeutic benchmarks across the covered disease categories. Fig. 1 schematically illustrates the analytical framework of this review. The horizontal axis represents the spatial expansion from barrier surfaces to deep organs, while the vertical axis indicates the generational evolution from passive mechanical breaching (Generation I) to microenvironment-adaptive, energy-coupled systems (Generation III). The intersection of these axes, which highlights material responsiveness at specific pathological niches, forms the core organizing principle of this review.

Fig. 1.

Schematic overview of bioactive microneedle (MN) platforms for disease management. The diagram illustrates the structural design and therapeutic applications of MN systems, depicting their evolution from local/barrier-surface therapy to systemic/deep-organ intervention. Three core dimensions are integrated: advanced materials, stimuli-responsive mechanisms, and therapeutic cargo delivery.

The broad scope of this review, spanning twenty disease domains from psoriasis to schizophrenia, inevitably limits the depth of coverage for individual conditions. Our objective is not to provide an exhaustive discussion of each indication, but to identify cross-cutting engineering principles and translational patterns that emerge from comparative analyses across diverse pathologies. Accordingly, each disease section prioritizes representative examples that illustrate generational transitions (Generation I to III) or specific responsive-material strategies, rather than cataloging all published studies.

The following sections follow the spatial-therapeutic axis established in Fig. 1. Section 2 examines MN applications across various disease domains, progressing from barrier-surface pathologies (cutaneous disorders, Section 2.1) to mucosal and metabolic conditions (Sections 2.2-2.3), and finally to systemic and deep-tissue diseases (oncology, ophthalmology, musculoskeletal, cardiovascular, neurological, and other emerging indications, Sections 2.4-2.9). Section 3 synthesizes cross-cutting translational challenges and outlines future directions for intelligent, adaptive MN platforms.

2. Microneedle applications in disease treatment

2.1. Applications of MNs in cutaneous disorders

The skin functions as a primary biological barrier, protecting the body against exogenous physical, chemical, and biological stressors. However, this barrier property limits the passive absorption of most topically applied therapeutics, with only an estimated 10-20% of the initial dose typically absorbed. Despite these limitations, cutaneous tissue can function as a pharmacokinetic reservoir for specific formulations, facilitating sustained local release and reducing the dosing frequency of agents with short systemic half-lives [45]. Consequently, developing advanced transdermal systems to enhance local bioavailability is essential for optimizing therapeutic efficacy while mitigating systemic off-target effects [46].

Over the past few decades, various strategies have been developed to bypass the SC, the primary rate-limiting barrier of the skin. These include chemical penetration enhancers [47,48], iontophoresis [48], electroporation [49], and sonophoresis [50]. Among these strategies, MN technology has gained significant attention. Its advantages include the delivery efficiency of invasive methods combined with minimal pain, enabling self-administration and reducing the generation of biohazardous sharps waste [51]. By creating transient aqueous microchannels within the SC, MNs provide an intermediate approach between traditional intradermal injections and topical applications, improving dosing precision and patient compliance [2].

The clinical importance of such innovations is evident given the global burden of skin diseases, which affect approximately one-third of the population and impose a substantial socioeconomic burden [52]. Refractory conditions, ranging from alopecia and psoriasis to malignant melanoma and chronic cutaneous infections, remain challenging to treat with standard-of-care protocols. In this context, MN platforms offer distinct advantages by facilitating deep-tissue deposition and permeation, while also promoting tissue regeneration [53], modulating localized immune responses [54], and supporting the structural restoration of damaged skin [55]. These capabilities make MN technology a valuable approach for addressing current therapeutic limitations in dermatology.

2.1.1. Applications of MNs in psoriasis

Psoriasis is a chronic, relapsing autoimmune dermatosis characterized by hyperkeratosis, which leads to a thickened SC, dense infiltration of immune cells (notably T cells and dendritic cells) into the dermis and epidermis, and a sustained release of pro-inflammatory cytokines [56]. Although corticosteroids and systemic immunosuppressants are clinically available, traditional topical formulations have limited bioavailability (less than 10%) due to the hyperkeratotic plaque barrier, while oral administration often causes off-target adverse effects such as hepatotoxicity [57,58]. To address these challenges, bioactive MN platforms provide a combined physical and biochemical intervention. They mechanically penetrate the thickened SC to form transient aqueous microchannels [56], facilitate direct targeting of intradermal and epidermal immune cells at the lesion site [57], and enable controlled drug release kinetics through stimuli-responsive or nanoconfined matrices. This approach effectively suppresses local inflammation while minimizing systemic exposure [58].

Initial efforts in MN-mediated psoriasis therapy focused on improving the delivery of conventional small-molecule therapeutics to replace hypodermic injections. For instance, Du et al. [59] developed hyaluronic acid (HA)-based dissolving MNs for methotrexate (MTX) delivery, demonstrating that localized administration could reduce epidermal thickening and cytokine expression while avoiding the systemic side effects of oral dosing. To enhance transport via lymphatic networks, Wang et al. [60] incorporated human serum albumin nanoparticles (HSA NPs) into the HA-MN matrix, utilizing the lymphatic transport of these particulate carriers to more effectively suppress immune cell activation. To extend the duration of small-molecule delivery and overcome the rapid clearance of free drugs, Du et al. [61] later developed a composite platform encapsulating MTX within chitosan-coated mesoporous silica nanoparticles (MTX@HMSN/CS). This system facilitates deep tissue penetration and provides sustained, programmed drug release (Fig. 2a) [61].

Fig. 2.

(a) Schematic diagram of MTX@HMSN/CS in the treatment of psoriasis. Reproduced with permission [61]. Copyright 2024 Journal of Materials Chemistry B. (b) Schematic illustration of the 3D-printed perforated MN arrays in treating psoriasis. Reproduced with permission [62]. Copyright 2023 Science Advances. (c) Schematic illustration of the mechanically robust supramolecular TA-Loaded HPCD DMN for the effective treatment of the IMQ-Induced psoriasis-like mouse model. Reproduced with permission [63]. Copyright 2023 ACS Applied Materials & Interfaces. (d) The drug delivery system of CPM nanoparticles combined with MAPs for rapid drug deposition and local sustained intradermal delivery in psoriasis. Reproduced with permission [64]. Copyright 2024 Molecular Pharmaceutics. (e) Schematic design of the application of mAbs-loaded photothermal responsive MN arrays for psoriasis treatment. Reproduced with permission [56]. Copyright 2022 Advanced Functional Materials. (f) Schematic of SLE MN Preparation, including exosome extraction and MXene preparation, and (g) Diagram of the subcutaneous light enhancement and immunomodulation mechanism of SLE MNs. Reproduced with permission [65]. Copyright 2025 ACS Applied Materials & Interfaces.

While nanoconfined small-molecule reservoirs can delay drug clearance, long-term remission in chronic autoimmune dermatosis often requires interventions that adapt to the dynamic immune microenvironment. Consequently, recent studies have integrated living therapeutics into the MN matrix, transitioning the arrays from passive drug carriers to active immunomodulatory platforms. For example, Zhang et al. [62] developed a 3D-printed perforated MN system to deliver regulatory T cells (Tregs) directly into psoriatic lesions (Fig. 2b). By maintaining cell viability for over 48 h and promoting fatty acid oxidation (FAO), this platform enhances the immunoregulatory function of Tregs, offering a localized alternative to systemic immunosuppression [62]. In parallel, for the transdermal delivery of highly lipophilic agents, material strategies have focused on supramolecular engineering. Wang et al. [63] used cyclodextrin-based MNs to encapsulate triamcinolone acetonide (TA) (Fig. 2c), improving the transdermal flux of this hydrophobic glucocorticoid through host-guest interactions. Similarly, to optimize the delivery of lipophilic vitamin D3 derivatives, Dai et al. [64] designed a trilayer dissolving microarray patch containing calcipotriol nanosuspensions. This system alleviated scaling and erythema in imiquimod (IMQ)-induced models by enhancing sustained intradermal drug deposition (Fig. 2d) [64].

Progressing from diffusion-controlled systems to on-demand interventions, recent MN research has incorporated stimuli-responsive materials and optical components. Wu et al. [56] combined MXene nanosheets with IL-17 inhibitors to create a photothermal-responsive patch (Fig. 2e). Under NIR irradiation, the light-triggered release of biologics synergistically suppressed keratinocyte hyperproliferation. To improve light penetration for deeper photothermal therapy, Zhao et al. [65] developed an optical MN platform (SLE MNs) with an ultra-transparent support structure (Fig. 2f and g). This design increases light transmission efficiency for the photothermal ablation of basal lesions while simultaneously promoting exosome-mediated immunomodulation.

To summarize these therapeutic approaches, Moawad et al. [44] recently reviewed the clinical translation of anti-psoriatic MN technologies. They discussed how advanced platforms, including those with ROS-responsive matrices, living microorganisms, and gene-editing vectors, can achieve autonomous immunomodulation while overcoming the mechanical barriers of psoriatic lesions [44]. This review highlights scalable sterile manufacturing and regulatory consensus as key requirements for future clinical translation [44].

Despite these preclinical advances, several methodological limitations must be addressed. First, the IMQ-induced murine model, used in most reviewed studies, primarily replicates the inflammatory phenotype of psoriasis but does not fully capture its autoimmune etiology involving IL-23/Th17 axis dysregulation. Therefore, the efficacy of stimuli-responsive MNs in human plaques, which have a thicker SC and a distinct immune microenvironment, requires further validation. Second, the long-term viability and functional stability of living therapeutic cargoes (e.g., Tregs, M2 exosomes) within dissolving matrices under ambient storage conditions are rarely reported, as most studies use freshly prepared formulations. Third, there is a lack of head-to-head comparative studies against established systemic biologics (e.g., secukinumab, ixekizumab). Without these comparisons, claims of superiority over conventional treatments remain unverified. Future investigations should prioritize clinically relevant endpoints, such as PASI-75 response rates and histological resolution, rather than relying solely on surrogate markers like epidermal thickness reduction in rodent models.

As summarized in Table 1, the integration of nanomedicine, bioactive materials, and responsive design has established MNs as a versatile platform for psoriasis management. However, their potential as a safer and more effective alternative to conventional therapies depends on addressing the translational challenges discussed above, particularly the need to validate efficacy in clinically representative models and against established therapeutic benchmarks.

Table 1.

Applications of microneedles in Psoriasis.

Research Field	MN Formulation/Designation	Drug Delivered	Function	References
Enhanced Small-Molecule Delivery	MTX + HA MN	Methotrexate (MTX)	HA matrix dissolves to release MTX, inhibiting epidermal hyperplasia and inflammatory cytokine expression	[59]
Enhanced Small-Molecule Delivery	MTX + HSA/HA MN	Methotrexate (MTX) encapsulated in albumin nanoparticles	HM enhances stable drug transport to lymph nodes, suppressing immune cell activation and prolonging therapeutic effects	[60]
Enhanced Small-Molecule Delivery	MTX@HMSN/CS MN	Methotrexate (MTX) loaded in chitosan-coated mesoporous silica nanoparticles	Microneedles penetrate thickened epidermis, and nanoparticles enable slow, sustained MTX release to inhibit Th17 cell differentiation and inflammation	[61]
Cellular Therapy	Treg-MN	Living Regulatory T cells (Tregs)	MN provides a survival microenvironment for T cells (Tregs), promotes their infiltration into lesions, inhibits pro-inflammatory factors, and enhances fatty acid oxidation (FAO).	[62]
Hydrophobic Drug Delivery	HPCD-TAMN	Triamcinolone acetonide complexed with cyclodextrin	Cyclodextrin encapsulates hydrophobic TA to enhance transdermal absorption and exert anti-inflammatory effects	[63]
Hydrophobic Drug Delivery	CPM NSs-MAP	Calcipotriol (CPM) nanosuspensions	Optimizes transdermal delivery of vitamin D3 derivatives to improve drug deposition in the skin and patient compliance	[64]
Stimuli-Responsive Therapy	MXene/IL-17 Inhibitor MN	Interleukin-17 (IL-17) biologic inhibitors + MXene nanosheets	NIR light triggers rapid drug release (IL-17 biologic inhibitors) to suppress keratinocyte hyperproliferation and inflammatory cytokine levels	[56]
Stimuli-Responsive Therapy	SLE MNs	M2 macrophage-derived exosomes + Multi-layered Ti3C2TX Mxene	Improves light transmission efficiency for deeper skin penetration and targeted photothermal treatment of basal psoriatic lesions	[65]

2.1.2. Applications of MNs in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 15%-20% of children and 3% of adults globally [66]. Clinically, it presents as a cycle of xerosis, pruritus, and intense erythema, frequently leading to chronic sleep deprivation and a significant decline in patient quality of life [67]. The complex pathogenesis of AD is characterized by a Th2-polarized immune response that triggers eosinophil and mast cell activation, while Th22-derived interleukin-22 (IL-22) concurrently compromises skin barrier integrity [68]. Despite the availability of various pharmacological options, conventional topical formulations often fail to provide sustained relief due to poor adherence and localized discomfort, mirroring the clinical challenges seen in psoriasis management [69]. To overcome these limitations, MN platforms have emerged as an effective strategy, offering improved drug bioavailability, localized specificity, and the capacity to act as immunomodulatory scaffolds that concurrently address inflammation and oxidative stress.

The development of MN-based AD therapy has transitioned from passive delivery vehicles to autonomous, theranostic systems. Initial efforts focused on overcoming the penetration barriers of refractory lesions; for example, Jang et al. [67] engineered dissolving microneedles (DMNs) to deliver high-dose corticosteroids. By utilizing a TA suspension and optimizing the polymer matrix via ultrasonic processing, this platform successfully suppressed keratinocyte inflammatory pathways and restored essential barrier proteins. Subsequently, research has shifted toward bi-functional and long-term management strategies. A notable advancement by Zhang et al. [70] involved bilayer MN arrays integrating Prussian blue nanoparticles (CET@PB NPs) for ROS scavenging with live Bacillus subtilis in the backing layer (Fig. 3a and b). This biotic-abiotic combination simultaneously mitigates oxidative stress and inhibits Staphylococcus aureus colonization, extending the therapeutic effect for over nine days.

Fig. 3.

(a) Schematic illustration of the MN arrays composition. (b) Schematic of the double-layered Bs/CET@PB MN array for treating AD through anti-bacteria, ROS scavenging, anti-inflammation, itch relieving, and skin barrier improving effects [70]. Reproduced with permission. Copyright 2025 Small. (c) Schematic illustration of application MNs for the treatment of AD, which inhibits ROS and oxidative stress inside the affected region and suppresses inflammatory reactions [71]. Reproduced with permission. Copyright 2024 Nano Today. (d) PLA-Pt MN array containing two PLA-Pt MN arrays. t-EMNP containing the PLA-Pt-PPy MN array and PLA-Pt MN array [46]. Reproduced with permission. Copyright 2022 ACS Applied Materials & Interfaces. (e) Schematic illustration of Inflammation-responsive double-layer microneedles for recurrent atopic dermatitis treatment [72]. Reproduced with permission. Copyright 2023 International Journal of Pharmaceutics.

To improve targeting precision, advanced MN systems have incorporated stimuli-responsive modules for on-demand intervention. Zhang et al. [71] introduced a polydopamine (PDA) nanozyme MN system that leverages the photothermal conversion and intrinsic antioxidant properties of PDA to trigger drug release via NIR light (Fig. 3c). Similarly, Yang et al. [46] utilized conductive PLA-Pt-PPy arrays to achieve electro-responsive control over drug release kinetics, providing precise temporal regulation (Fig. 3d).

As an advanced approach in adaptive therapeutics, Song et al. [72] engineered an inflammation-responsive bilayer MN patch capable of sensing the localized inflammatory microenvironment. Utilizing a gelatin methacryloyl (GelMA)-based architecture, this platform autonomously triggers the release of vitamin D3 upon detecting physiological cues associated with disease flare-ups (Fig. 3e) [72]. This research team subsequently coupled NIR-controlled TA release with the prolonged moisturizing effects of a HA backing layer [73]. By integrating black phosphorus quantum dots (BPQDs) for triggered delivery with the hydrating properties of HA, the platform addresses both the underlying pathological cascades and the symptomatic xerosis characteristic of AD. The technological milestones summarized in Table 2 provide a detailed overview of MN-mediated interventions for AD, demonstrating a progressive shift from simple corticosteroid delivery to complex, microenvironment-adaptive platforms.

Table 2.

Applications of microneedles in Atopic Dermatitis.

MN Formulation/Designation	System	Key Components	Mechanism of Action	References
TA-DMN	High-dose Dissolving MN	Triamcinolone acetonide (TA), polymer matrix	Suspension-based formulation enables high drug loading; TA inhibits keratinocyte inflammatory pathways and restores barrier proteins.	[67]
CET@PB NPs-MN	Bio-nano Synergistic Bilayer MN	Prussian blue (PB) NPs, B. subtilis (live bacteria)	PB NPs scavenge ROS to alleviate oxidative stress; Live B. subtilis inhibits S. aureus colonization to rebalance the skin microbiome.	[70]
PDA HAMA/HA-MN	Photothermal-responsive Nanozyme MN	HA/HAMA, PDA nanozymes	NIR-triggered photothermal effect facilitates MN dissolution and drug release; PDA nanozymes neutralize ROS to mitigate oxidative damage.	[71]
PLA-Pt-PPy MNs	Electro-responsive Conductive MN	PLA-Pt, Poly(pyrrole) (PPy) arrays	Electrical stimulation precisely regulates drug release kinetics; significantly reduces epidermal thickening and pro-inflammatory cytokines.	[46]
inflammation-responsive bilayer MN patch	Inflammation-responsive Bilayer MN	GelMA needle tip, Vitamin D3, HA backing	Inflammatory microenvironment triggers autonomous Vitamin D3 release from GelMA; suppresses mast cell infiltration and prevents AD relapse.	[72]
TA/BPQDs MNs	Multifunctional “Moisturizing + NIR” MN	Black phosphorus quantum dots (BPQDs), TA, HA backing	HA backing provides long-term hydration; BPQDs enable NIR-controlled TA release to reduce epidermal thickness and inflammation.	[73]

Although the transition from passive corticosteroid delivery to microenvironment-adaptive platforms represents significant progress, several challenges remain. The reliance on MC903- or DNFB-induced murine models, which exhibit Th2-skewed inflammation but lack the complex skin barrier genetic defects (e.g., filaggrin mutations) characteristic of human AD, limits clinical predictability. Furthermore, while biotic-abiotic systems offer theoretical microbiome modulation advantages, the immunogenicity risks of introducing live bacterial payloads into already dysregulated skin, particularly in pediatric populations, require further evaluation. Stimuli-responsive on-demand systems also introduce usability challenges: patients with active AD flares may lack the compliance or technical capacity to operate external triggering devices during symptomatic episodes.

Ultimately, the maturation of MN-mediated AD therapy reflects a shift toward microenvironment-adaptive interventions. However, future clinical translation depends on addressing the limitations identified above. Rather than pursuing increasingly complex multi-responsive architectures, we suggest that the most promising near-term pathway lies in closed-loop platforms capable of autonomous biomarker monitoring and preemptive drug release, combined with ultra-soft, bio-elastic arrays that minimize mechanical irritation on hypersensitive skin. This combined focus on autonomous sensing without patient-operated triggers, and biomechanical compatibility with fragile skin, offers a more practical foundation for long-term patient-centric care than current biotic-abiotic or energy-dependent paradigms.

2.1.3. Applications of MNs in hypertrophic scars

Hypertrophic scarring (HS) is a chronic fibroproliferative disorder resulting from dysregulated cutaneous wound healing, characterized by persistent fibroblast activation and excessive extracellular matrix (ECM) deposition [[74], [75], [76]]. Although conventional interventions, including surgical revision, silicone sheeting, and radiotherapy, remain standard clinical treatments [77], their efficacy is often limited by prolonged treatment durations and high recurrence rates [78]. To address these challenges, MN technology has emerged as a promising therapeutic strategy. By penetrating the dense scar tissue to establish physical microchannels, MNs significantly enhance the localized bioavailability of antifibrotic agents while mitigating systemic toxicity, providing a targeted approach for scar management.

The development of MN-based HS therapy has transitioned from simple solubility enhancement to the creation of multifunctional platforms. Initial innovations focused on overcoming the pharmacological barriers of poorly soluble drugs. For instance, Wu et al. [79] engineered biomimetic cyclodextrin MOF MNs, which achieved a 30-fold increase in quercetin solubility (Fig. 4a). This system effectively attenuated collagen deposition by co-regulating the Wnt/β-catenin and JAK2/STAT3 signaling axes. Given the dynamic nature of scar maturation, research has shifted toward sequential release kinetics. Yang et al. [77] developed a bilayer MN array that synergistically delivered 5-fluorouracil (outer layer) for prolonged anti-proliferation and triamcinolone acetonide (inner layer) for rapid anti-inflammation, effectively downregulating the TGF-β2/Smad axis (Fig. 4b and c).

Fig. 4.

(a) Schematic illustration of fabrication and administration of BSP-MNs-QUE@HSF/CDF [79]. Reproduced with permission. Copyright 2021 ACS Nano. (b) Schematic illustration of an HS model in rabbit ear, the design of the BMN with 5-Fu in the tip layer and TA in the tail layer of the needle and (c) drug delivery with biphasic release profile to scar lesion using BMN for synergic HS treatment [77]. Reproduced with permission. Copyright 2021 Bioactive Materials. (d) Schematic illustration of HS in rabbit ears, the application of miR-141OE-Exos@DMNAs and its potential role in the treatment of HS [80]. Reproduced with permission. Copyright 2024 Small. (e) Schematic illustration of the fabrication process of a separating MN array via a step-by-step method and Schematic illustration of the drug-loaded MNs on HS treatment [81]. Reproduced with permission. Copyright 2024 Nature Communications.(f) Schematic diagram of a novel bilayer microneedle patch (DC-MNs) loaded with dexamethasone and colchicine for differential dual-release in the treatment of pathological scars [82]. Reproduced with permission. Copyright 2025 Biomaterials.

As the molecular mechanisms of fibrosis are further elucidated, MN-mediated interventions have expanded to target programmed cell death and epigenetic regulation. Zhao et al. [83] constructed an AgNC/TRG/ZIF-8 MN array designed to induce ferroptosis in myofibroblasts by promoting lipid ROS accumulation and inhibiting GPX4. Simultaneously, gene-silencing strategies have been integrated into MN platforms; Meng et al. [80] encapsulated engineered exosomes enriched with miR-141-3p into dissolving MNs to target TGF-β2 and suppress fibroblast-to-myofibroblast transdifferentiation (Fig. 4d). Furthermore, the pathological microenvironment can be actively remodeled through stimuli-responsive MNs, such as the ROS- and MMP-sensitive patches developed by Yang et al. [81], which trigger drug release specifically within the enzymatic niche of the lesion (Fig. 4e).

Recent advancements integrate multidisciplinary approaches, combining material science with energy-driven physical strategies. Xu et al. [82] optimized dual-release kinetics using a hybrid HA/poly(lactic-co-glycolic acid) PLGA matrix for the coordinated delivery of dexamethasone and colchicine (Fig. 4f). Beyond biochemical modulation, the incorporation of external physical fields has introduced additional therapeutic mechanisms. Gao et al. [84] proposed an iontophoretic MN array powered by an integrated paper battery, combining physical penetration with active electro-transport. Detailed applications of microneedles for treating hypertrophic scarring are summarized in Table 3.

Table 3.

Applications of microneedles in Hypertrophic Scar.

General Approach	MN Designation	Key Components	Mechanism of Action	References
Targeted Solubility Enhancement	BSP-MNs-QUE@HSF/CDF	Quercetin (QUE), Cyclodextrin MOF	Cyclodextrin increases QUE solubility by > 30-fold; targets Wnt/β-catenin and JAK2/STAT3 pathways to inhibit collagen deposition.	[79]
Biphasic Dual-Drug Release	TA -5-Fu-BMN	5-Fu (outer), TA (inner), HA/CD matrix	Sequential synergy: Outer layer releases 5-Fu slowly (anti-proliferation) while inner layer releases TA rapidly (anti-inflammation) via TGF-β2/Smad downregulation.	[77]
Ferroptosis Induction	AgNC/TRG/ZIF-8 MN	AgNC, TRG, ZIF-8 (MOF)	Induces myofibroblast ferroptosis by promoting lipid ROS generation, depleting GSH, and inhibiting GPX4 activity; reduces α-SMA expression.	[83]
Precision Gene Therapy	miR-141-3pOE-Exos/DMN	miR-141-3p, Engineered Exosomes	Sustained release of exosomal miR-141-3p targets TGF-β2 to suppress fibroblast transdifferentiation and remodel scar architecture.	[80]
Stimuli-Responsive Prodrug Delivery	GelMA/5-FuA MN	GelMA, 5-FuA (prodrug)	Dual-responsive to high ROS and MMPs; scavenges pathological ROS and depletes MMPs to actively remodel the fibrotic microenvironment.	[81]
Optimized Kinetic Control	DC-MNs	HA (DXM), PLGA (Colchicine)	Biphasic profile: HA enables rapid DXM release for acute inflammation; PLGA ensures sustained Colchicine release to suppress chronic fibrosis.	[82]
Energy-Driven Delivery	PBIMNP	Paper battery, Phase-change materials	Self-powered iontophoresis increases transdermal efficiency to 90.19%; combines physical penetration with active electrophoretic drug driving.	[84]

The evolution from solubility enhancement to ferroptosis induction represents significant mechanistic progress; however, several critical constraints remain. The rabbit ear model, commonly used in these studies, exhibits fundamentally different wound healing kinetics compared to human skin, particularly in collagen remodeling and myofibroblast contractility, which limits the clinical predictability of efficacy claims. Furthermore, heavy metal-containing nanomaterials (e.g., AgNCs, ZIF-8 MOFs) raise unresolved biosafety concerns: the chronic biodistribution, renal clearance, and systemic accumulation of these materials in repeat-administration scenarios remain largely unexplored. Energy-dependent strategies also face clinical practicality challenges in scar management, where treatment spans months to years and patient compliance with powered devices is often poor.

Overcoming the resistance of fibrotic tissue remains a primary challenge. However, rather than pursuing increasingly complex nanocatalytic mechanisms with undefined long-term safety, we propose that the field should focus on clinically validated anti-fibrotic payloads delivered through mechanically robust, metal-free matrices. This approach leverages the synergy between biochemical modulation and external energy fields to disrupt the dense collagen matrix. By coupling advanced material science with mechanobiology, MN arrays can transition from simple delivery tools to active scaffolds capable of promoting complete structural restoration, provided that biomechanical robustness and biosafety are prioritized over mechanistic novelty.

2.1.4. Applications of MNs in acne

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit that primarily affects adolescents but increasingly persists into adulthood [85,86]. In addition to physical symptoms such as erythema and comedones, the associated aesthetic impairment often causes significant psychological distress [85,86]. Although systemic antibiotics and topical retinoids are standard clinical treatments [87,88], their efficacy is often limited by the skin barrier, which prevents sufficient active ingredients from reaching deep lesions [[89], [90], [91]]. To overcome these delivery challenges, MN technology has been developed to facilitate localized drug deposition while minimizing systemic side effects [8]. Recent developments have transitioned from single-drug reservoirs to multi-agent compartmentalization and stimuli-responsive platforms, enabling the controlled release of diverse therapeutics.

Early anti-acne MN platforms utilized environment-responsive materials to target the acidic acne microenvironment. For example, Wen et al. [92] developed ZIF-8-ICG@MNs that encapsulate indocyanine green within pH-responsive MOFs. This system undergoes selective degradation at pH ∼ 5.5 to release Zn²⁺, while 808 nm laser irradiation triggers ROS generation for antibacterial and anti-inflammatory effects (Fig. 5a). In vitro and in vivo experiments demonstrated NF-κB pathway inhibition and significant alleviation of skin inflammation. However, the reliance on a single ROS mechanism and external laser equipment has prompted the exploration of multi-modal strategies with improved tissue penetration and clinical practicality.

Fig. 5.

(a) Schematic illustration of the construction of multifunctional ZIF-8-ICG@MNs for amplified Chemo-Photodynamic therapy against acne vulgaris [92]. Reproduced with permission. Copyright 2021 ACS Applied Materials & Interfaces. (b) Schematic diagram of ZnTCPP@ZnO MNs therapy [93]. Reproduced with permission. Copyright 2023 Science Advances. (c) Schematic illustration of DBMNPs for acne treatment [94]. Reproduced with permission. Copyright 2025 Microsystems & Nanoengineering.(d) Schematic illustration of the preparation process of DOP/CCF/PLGA@Adap-MN and(e) Schematic representation of the therapeutic effects of DOP/CCF/PLGA@Adap-MN for acne treatment [95]. Reproduced with permission. Copyright 2025 International Journal of Biological Macromolecules.

To address the limitations of monotherapy, subsequent systems have incorporated energy-responsive and structurally programmed designs. Xiang et al. [93] designed ZnTCPP@ZnO MNs that achieve 99.73% antibacterial efficiency through ultrasound-triggered ROS generation, while the released Zn²⁺ concurrently promotes fibroblast proliferation and tissue remodeling (Fig. 5b). This approach offers deeper penetration and lower phototoxicity than photodynamic therapy, although energy dependence remains a clinical constraint.

In addition to energy-responsive approaches, structural innovations have enabled the co-delivery of multiple agents. Zhang et al. [94] engineered dissolving bubble microneedle patches (DBMNPs) with hollow micro-bubble architectures within HA stems (Fig. 5c). This 3D compartmentalization allows for the co-delivery of hydrophilic and hydrophobic agents, including dipotassium glycyrrhizinate, salicylic acid, and quaternium-73 (pionin), providing both acute symptomatic relief and sustained antimicrobial intervention against Cutibacterium acnes. Parallel to these structural designs, Li et al. [95] developed a bio-sourced matrix using Dendrobium officinale polysaccharide (DOP) as the structural backbone. This matrix intrinsically exerts antioxidant and anti-inflammatory activities while delivering embedded flavonoids and adapalene PLGA nanoparticles to restore epidermal barrier integrity (Fig. 5d and e).

Recent studies have also focused on synergistic photothermal-chemotherapy and autonomous pathological adaptation. Wang et al. [96] developed E@P-EO-HA MNs that utilize the intrinsic photothermal properties of polydopamine under NIR irradiation for sebaceous gland ablation, while the sustained release of eugenol inhibits C. acnes and modulates immune responses (Fig. 6a). This combined photothermal and chemotherapeutic approach does not require external energy storage, improving clinical convenience. Building on this polydopamine framework, Wang et al. [97] recently engineered a hierarchical core-backing composite MN array (Cur-MPDA + Cur@HA/FPS MNs). This system introduces pathological pH-responsiveness, accelerating curcumin diffusion under acidic acne conditions (pH 5.0), while achieving rapid hyperthermia under 808 nm laser irradiation (Fig. 6b). This dual-responsive architecture autonomously adapts to lesion-specific biochemical cues.

Fig. 6.

(a) E@P-EO-HA MNs promote acne healing through a synergistic action of destroying the sebaceous gland, antibacterial activity, and anti-inflammatory activity [96]. Reproduced with permission. Copyright 2024 ACS Applied Materials & Interfaces. (b) The therapeutic application of Cur-MPDA + Cur@HA/FPS microneedles combined with NIR irradiation in acne vulgaris facilitates local drug delivery to enhance ROS scavenging and Eradicate P. acnes and suppresses inflammation [97] Reproduced with permission. (c) The synthesis process of PDA-JAKi MN and the mechanism mediated by PDA-JAKi MN [98].Reproduced with permission. Copyright 2025 Journal of Nano biotechnology.

The progression from single-mechanism to dual-responsive systems demonstrates significant technical advancement; however, several challenges remain regarding clinical translation. A primary concern with photothermal strategies is the depth of the sebaceous gland, which resides at 2-4 mm. This depth exceeds the effective penetration of most MN-mediated optical modalities (<1 mm), suggesting that reported glandular destruction may actually involve collateral dermal damage. Furthermore, the use of murine ear models, which lack human pilosebaceous architecture and hormonal profiles, limits the external validity of these findings. Additionally, none of the reviewed studies addressed the mitigation of antibiotic resistance; the use of antimicrobial peptides or ROS-generating agents at sub-lethal doses may inadvertently select for resistant C. acnes.

As summarized in Table 4, the development of anti-acne MNs has progressed through three distinct generations. However, rather than focusing solely on increasingly complex energy-coupled systems, future research should prioritize the transdermal delivery of non-antibiotic anti-inflammatory agents, such as JAK inhibitors and IL-1α antagonists. This strategy avoids the penetration-depth limitations and antimicrobial resistance concerns while directly addressing the inflammatory pathogenesis of acne. Although each developmental stage has addressed previous limitations, manufacturing scalability and long-term stability remain critical translational challenges for all MN architectures.

Table 4.

Applications of microneedles in Acne.

Formulation Strategy	Drug/Cargo Delivered	Mechanism of Action	Advantages	Limitations	References
ZIF-8-ICG@MNs	ZIF-8 MOF, ICG	pH-responsive degradation +808 nm laser ROS	pH-targeting; dual antibacterial/anti-inflammatory	Single ROS mechanism; external laser required	[92]
ZnTCPP@ZnO MNs	Zinc porphyrin MOF, ZnO	Ultrasound-triggered ROS	99.73% antibacterial; deeper penetration; lower phototoxicity	Energy-dependent; portability limited	[93]
DBMNPs	HA, hollow micro-bubbles, multiple drugs	Passive dissolution	3D spatial partitioning; rapid + sustained release	Complex fabrication; burst release risk	[94]
DOP/CCF/PLGA@Adap-MN	DOP, CCF, adapalene-PLGA NPs	Bioactive matrix intrinsic activity	Intrinsic antioxidant/anti-inflammatory; barrier restoration	Batch variability; stability concerns	[95]
E@P-EO-HA MNs	PDA, eugenol, HA	NIR-responsive PDA photothermal	No external energy storage; dual action	Photothermal depth limitation; thermal risk	[96]
Cur-MPDA + Cur@HA/FPS MNs	MPDA, curcumin, fucoidan/HA	pH-responsive diffusion + 808 nm hyperthermia	Pathological pH-adaptation; target-specific	Preclinical stage; long-term safety pending	[97]

2.1.5. Applications of MNs in vitiligo

Vitiligo is an acquired chronic pigmentary disorder characterized by the progressive loss of functional melanocytes, affecting 1%-2% of the global population [99,100]. Pathologically, the condition arises from the disruption of the melanocyte-keratinocyte (M −K) unit, where impaired melanin synthesis and transfer lead to depigmented macules [101]. While current treatments, including corticosteroids, calcineurin inhibitors, and phototherapy, aim to arrest disease progression, their efficacy remains inconsistent due to the complex interplay of oxidative stress, autoimmunity, and localized inflammation [[102], [103], [104], [105]]. In this context, MN platforms offer a combined strategy: the physical micro-trauma induces a wound-healing response that recruits hair follicle melanocyte stem cells, while the transdermal microchannels enable the targeted delivery of melanogenesis-promoting factors directly to the dermal-epidermal junction.

Recent technological advancements have shifted from single-drug delivery toward multi-targeted regulation. Initial research focused on the immunological and regenerative axes; for instance, Liang et al. [106] developed dual-crosslinked dextran hydrogel MNs (HGDexMA MNs) to co-deliver the JAK inhibitor tofacitinib and the pro-melanogenic peptide α-MSH. By simultaneously attenuating JAK-STAT-mediated immune responses and stimulating pigment regeneration, this system significantly accelerated repigmentation in both the epidermis and hair follicles. However, because oxidative stress is often the primary trigger for melanocyte apoptosis, integrating potent radical-scavenging modalities became necessary.

To address this oxidative stress, Li et al. [98] engineered polydopamine-loaded hydrogel MNs (PDA-JAKi MNs) incorporating biomimetic nanoparticles to neutralize ROS (Fig. 6c). This platform interrupts the pathogenic cascade by inhibiting HMGB1 release, a key alarmin in vitiligo, and the subsequent infiltration of CD8⁺ T cells. By protecting the M − K unit from oxidative injury while maintaining local immunosuppression, this approach achieves enhanced restoration of melanocyte density compared to early dual-drug systems.

Although the combined strategy of physical micro-trauma and targeted drug delivery is conceptually sound, the current evidence base has methodological limitations. Depigmentation models, such as monobenzone-induced or spontaneous murine vitiligo, fail to fully recapitulate the autoimmune-mediated melanocyte destruction seen in over 90% of human cases, which may overestimate clinical translatability. A notable inconsistency also persists: while oxidative stress is considered a primary trigger, the relative contributions of ROS scavenging versus JAK-STAT inhibition remain unclear in head-to-head studies. Furthermore, anatomical specificity, particularly the resistance of acral and mucosal lesions, has been largely ignored, with most studies targeting easily accessible truncal skin.

Future clinical translation requires addressing these gaps. Rather than making generalized claims of superior repigmentation without lesion stratification, we suggest that research should focus on follicular niche-targeting MNs that mobilize quiescent melanocyte stem cell reservoirs, combined with standardized outcome metrics (e.g., VASI scores, Wood's lamp assessment) to replace subjective photographic evaluation. Achieving durable repigmentation in refractory acral lesions requires both precise follicular modulation and validated long-term stability across diverse anatomical sites, objectives that remain unmet in current platforms.

2.1.6. Applications of MNs in melanoma

Cutaneous malignancies are the most common type of cancer globally, with malignant melanoma being the most aggressive due to its rapid progression and high therapeutic resistance [107,108]. Although melanoma accounts for a small percentage of skin cancer cases, it causes the majority of skin cancer-related deaths [109,110]. While surgical excision is the first-line treatment, clinical outcomes are often limited by difficult margin assessments, surgical complications, and poor patient compliance following functional or aesthetic impairment. To address these limitations, MN platforms have integrated external microenergy modalities, such as phototherapy [111,112], ultrasound [113,114], and magnetic fields, to achieve non-invasive [115] and spatiotemporally controlled tumor ablation.

The combination of MN technology with chemodynamic therapy (CDT) and photodynamic therapy (PDT) provides an effective strategy to disrupt tumor redox homeostasis via the in situ generation of hydroxyl radicals (·OH) and ROS [116,117]. For example, Huang et al. [118] developed pH-responsive MNs (DHA@HPFe-MN) that utilize iron ions to activate dihydroartemisinin and protoporphyrin IX within the acidic tumor microenvironment (Fig. 7a and b). This localized catalytic cascade achieves significant tumor suppression with minimal systemic exposure. To further enhance synergistic effects, Chen et al. [124] combined self-amplified CDT with photothermal therapy (PTT) by encapsulating Cu2O nanoparticles, which drive Fenton-like reactions while enabling NIR-triggered thermal ablation.

Fig. 7.

(a) Schematic illustration of the fabrication of hydrogel-based DHA@HPFe-MN microneedles.and(b) Schematic illustration of the in vivo antitumor mechanism of DHA@HPFe-MN via oxidative stress amplification [118]. Reproduced with permission. Copyright 2021 Med. Sci. (c) Design principle of the NIR light-activatable dissolving MN system (MN-pB/I) for multimodal theragnostic application in melanoma. (d) The fabrication process of (MN-pB/I) MN patches [119]. Reproduced with permission. Copyright 2019 Adv Healthc Mater. (e) Schematic illustration of D/I@PATC MN patches for laser-triggered chemo-photothermal synergistic therapy of melanoma [120]. Reproduced with permission. Copyright 2021 Chem. Commun. (f) Working mechanism of the F-MN device composed of F-TENG and dissolving MN patch and (g) Illustrative diagram showing a MN patch to facilitate transdermal drug delivery to deep-seated tumors [121]. Reproduced with permission. Copyright 2021 Explorations. (h) The structure of a dual-layered microneedle rocket with thrusters and (i) Mechanisms of PcNP/TRA-HA-Tyr/CLG-MN for deep drug penetration and combination therapy [122]. Reproduced with permission. Copyright 2020 Mater Today Adv. (j) Schematic illustration of antimicrobial microneedle for photothermal-chemotherapy of melanoma [123]. Reproduced with permission. Copyright 2021 Adv. Funct. Mater.

Beyond localized intervention, the field is evolving toward precision visualization and real-time monitoring. For instance, Liu et al. [119] engineered NIR-activatable MNs (MN-pB/I) that pair ROS-responsive doxorubicin prodrugs with indocyanine green, facilitating fluorescence and photoacoustic dual-mode imaging to guide drug release (Fig. 7c and d). Similarly, the integration of AIE microparticles by Wang et al. [120] has enabled self-monitoring and pulsed drug release, achieving a 97% tumor inhibition rate (Fig. 7e).

Recent developments in melanoma management have shifted toward systemic immune activation and deep-tissue penetration. A recent study by Jiang et al. [125] demonstrated that MNs co-loaded with temozolomide and MnCl₂ can activate the cGAS-STING pathway, transforming the primary lesion into an in situ vaccine that suppresses distant pulmonary metastasis through immunogenic cell death (ICD). To overcome the physical barriers of deep-seated tumors, Wang et al. [121] introduced a self-powered MN system (F-MN) driven by a triboelectric nanogenerator (TENG) to facilitate electrophoretic drug transport (Fig. 7f and g). Other structural innovations, such as the rocket-shaped, enzyme-responsive MNs by Pan et al. (Fig. 7h and i) [122] and the polypyrrole-embedded arrays by Zhang et al. (Fig. 7j) [123], further illustrate the shift toward multi-responsive, highly biocompatible platforms. As summarized in Table 5, microneedles offer multiple approaches for melanoma treatment.

Table 5.

Applications of microneedles in Melanoma.

Therapeutic Approach	MN Formulation/Designation	Strategy of treatment	Action mechanisms	References
Chemo-Photodynamic Therapy	DHA@HPFe-MNs	CDT + PDT	pH-triggered Fe2+ release activates DHA for ROS generation; PpIX-loaded tips enhance photodynamic effect under NIR light.	[118]
Chemodynamic + Photothermal	MN@CuO2	CDT + PTT	CuO2 decomposes in acidic tumors to drive Fenton-like reactions and consume GSH; synergizes with NIR-induced hyperthermia.	[124]
NIR-Activatable Synergistic	MN-pB/I	Responsive Chemo + Phototherapy	ROS-responsive DOX prodrug and ICG enable fluorescence/PA dual-mode imaging guided release with photothermal ablation.	[119]
Light-Controlled Pulsatile	D/I@PATC-MN	Self-monitoring Chemo-PTT	AIE microparticles allow real-time fluorescence monitoring and pulsed DOX/ICG release for precise spatiotemporal control.	[120]
Chemo-Immunotherapy	TMZ/MnCl2@HMN	cGAS-STING Activation	TMZ triggers Immunogenic Cell Death (ICD); Mn2+ activates the cGAS-STING pathway to enhance systemic antitumor immunity	[125]
Electro-enhanced Delivery	F-MN	Self-powered Chemo-PDT	Triboelectric nanogenerator drives electrophoretic penetration; pH-responsive NPs release DOX/Ce6 in deep-seated tumors.	[121]
Deep Penetration Combination	PcNP/TRA-HA MN	ECM Remodeling + PDT	Enzyme-responsive bilayer structure degrades ECM; overcomes delivery barriers for localized TRA/PS.	[122]
Photothermal-Chemotherapy	PVACS/PPy MNs	Localized PTT + Chemo	Polypyrrole (PPy) NPs integrate photothermal ablation with chemotherapy for potent tumor clearance and high biocompatibility.	[123]

The integration of MN technology with CDT, phototherapy, and immunotherapy represents a significant development in the field; however, methodological limitations remain. The majority of studies employ subcutaneous B16-F10 xenografts, a model that lacks the desmoplastic stroma, elevated interstitial pressure, and immunosuppressive microenvironment of human melanoma. High tumor inhibition rates (e.g., 97% in AIE-based systems) rarely translate successfully to autochthonous or patient-derived models. A critical safety concern also affects photothermal-chemodynamic platforms: Fenton-generated hydroxyl radicals lack spatial selectivity, risking irreversible damage to adjacent dermal fibroblasts and melanocytes, which poses a potential secondary malignancy risk that no reviewed study has addressed. Furthermore, the in situ vaccine concept assumes that localized immunogenic cell death reliably generates systemic immunity; however, the immunosuppressive context of established melanoma (e.g., Treg infiltration, IDO expression) may abrogate this effect clinically.

The transition from localized ablation to systemic anti-tumor immunity represents a promising approach. However, rather than focusing solely on maximal local tumor ablation, we suggest that future success depends on shifting toward immune microenvironment remodeling. This involves prioritizing sustained low-dose immunomodulation over acute cytotoxic payloads, which risk inducing immunosuppression. Refining the synergy between nanocatalytic medicine and flexible bioelectronics must therefore emphasize long-term immunosafety and deep-tissue efficacy in immunocompetent, clinically representative models, rather than merely demonstrating tumor suppression in simplified xenografts.

2.1.7. Applications of MNs in skin wounds

Chronic cutaneous wounds remain a significant clinical challenge, characterized by impaired healing and a complex localized microenvironment. Managing these wounds requires a platform capable of addressing multiple pathological factors simultaneously. MN technology has emerged as a practical solution, evolving from simple drug delivery models to systems that actively modulate the wound microenvironment.

Early research in this area focused on combining antimicrobial efficacy with tissue repair. Zeng et al. [126] utilized a MOF integrated with dimethyloxalylglycine (DMOG) in a HA matrix to synchronize photodynamic therapy with the sustained release of pro-angiogenic factors (Fig. 8a). However, the clinical risk of secondary oxidative damage from exogenous ROS led to the development of redox-regulating nanozymes. Chen et al. [99] employed polydopamine-modified MnO₂ nanozymes to establish a cascade mechanism that scavenges excessive radicals while maintaining photothermal bactericidal activity, thereby protecting surrounding healthy tissue during sterilization (Fig. 8b).

Fig. 8.

(a) Schematic illustration of multifunctional MOF-based MN patch with chemo-photodynamic antimicrobial property and sustained release of growth factor for chronic wound healing [126].Reproduced with permission Copyright 2023 Advanced Healthcare Materials.(b) Schematic diagram of the application of PDA-modified MnO₂ NPs microneedle patch [99].Reproduced with permission Copyright 2021 Med Res Rev. (c) Schematic illustration of MgB₂ microparticles (MPs) integrated microneedle (MgB₂ MN) patches [127]. Reproduced with permission. Copyright 2024 Advanced Science.(d) Schematic illustration of the synthesis of RE@SA-Con A/SNO NPs and subsequent encapsulation in a MN patch and (e) Schematic illustration of the application of a MN patch loaded with RE@SA-Con A/SNO NPs for targeted and synergistic therapy of chronic wounds [128]. Reproduced with permission Copyright 2024 Advanced Materials. (f–g) Crosslinking mechanisms and structure of EBO-Gel [129]. Reproduced with permission Copyright 2024 Nature Communications.

The persistence of resistant biofilms and the inflammatory response triggered by bacterial debris (e.g., lipopolysaccharides, LPS) remain significant challenges. Recent innovations have shifted toward active bacterial trapping and targeted elimination. Shan et al. [127] used magnesium boride (MgB₂) to create a localized alkaline environment that inactivates pathogens and binds LPS, preventing the cytokine responses typically induced by necrotic bacteria (Fig. 8c). This targeting approach was further refined by Jin et al. through a Con A-mediated recognition mechanism (Fig. 8d and e) [128], and by Han et al., who utilized Ga³⁺-assisted oxidative stress amplification to penetrate and eradicate deep-seated biofilms (Fig. 8f and g) [129].

In parallel with biochemical innovations, the interfacial stability of MNs in exudative wound environments has gained increasing attention. The biomimetic adhesive microneedles (adhMNs) developed by Wu and Liu represent a notable shift in design strategy [130]. By utilizing a “dry-penetration, wet-adhesion” approach, where the needles remain rigid for insertion but undergo hydration-triggered interlocking, these patches maintain stable, prolonged in situ delivery despite the complex fluid dynamics of chronic wound exudates. The research outcomes summarized in Table 6 illustrate the functional diversification of MN arrays, highlighting their evolution from antimicrobial delivery vehicles to multi-targeted systems for comprehensive chronic wound management.

Table 6.

Applications of microneedles in Skin Wounds.

General Approach/Strategy	Key Components	Functions	Advantages	References
Chemo-PDT & Bioactive Release	HA, DMOG@PCN-224 MEM	Photodynamic sterilization; sustained growth factor release.	Reduces antibiotic dependence; synchronizes infection control with tissue repair.	[126]
Nanozyme-PTT & ROS Scavenging	GelMA, PDA-MnO2	Photothermal ablation; ROS scavenging via nanozymes.	Mitigates PTT-induced thermal damage; improves safety in infected wounds.	[99]
Alkaline Sterilization & Debris Trapping	MgB2 MN	Alkaline-mediated killing; capturing dead bacteria/debris.	Prevents debris-induced inflammation; highly effective against MRSA.	[127]
Targeted NO & Biofilm Disruption	RE@SA-Con A/S NO NPs	Targeted NO release; enzymatic biofilm removal.	Deep biofilm penetration; integrates anti-inflammatory and regenerative cues.	[128]
Oxidative Stress Amplification	BSPG (Ga3+-Bi2S3)	Light/pH-activated oxidative stress; biofilm elimination.	Overcomes biological barriers via amplified oxidative stress; promotes healing.	[129]
Biomimetic Wet-Tissue Adhesion	adhMNs	Ultra-strong adhesion; sustained deep drug delivery.	Superior wet-tissue fixation; hydrates/swells for controlled, long-term release.	[130]

The functional diversification of MN platforms for chronic wound management demonstrates progress in the field; however, critical translational barriers remain inadequately addressed. Preclinical studies almost exclusively employ monomicrobial Staphylococcus aureus or Pseudomonas aeruginosa challenges, whereas human chronic wounds harbor polymicrobial biofilms (typically 3-5 species) with established resistance profiles. This discrepancy limits the clinical relevance of claims regarding MgB₂-based sterilization or Con A-mediated targeting. adhMNs, while designed for exudative environments, have not been validated under high protease activity, a hallmark of non-healing wounds where enzymatic degradation may compromise wet-adhesion within days. Additionally, standard wound care prioritizes debridement, offloading, and moisture balance, yet few MN studies integrate these foundational elements.

Future progress depends on addressing these gaps rather than pursuing increasingly complex bio-interactive designs alone. We suggest that practical MN systems should complement, rather than replace, established wound care protocols. Integrating real-time diagnostic capabilities with biomechanical stabilization should only proceed after demonstrating non-inferiority to standard debridement and offloading protocols. The field risks over-engineering solutions for problems that are fundamentally clinical in nature, such as diabetic foot ulcer recurrence driven by hyperglycemia and mechanical pressure. Meaningful progress toward functional wound restoration requires aligning technological innovation with the established priorities of clinical wound care.

2.2. Applications of MNs in diabetic wound healing

Diabetes mellitus is a prevalent global health issue, with the patient population projected to reach 700 million by 2045. Among its complications, diabetic foot ulcers (DFUs) present a significant clinical challenge, affecting approximately 7.2% to 15% of diabetic individuals [37,38]. The pathological progression of DFUs is often complicated by secondary infections, which occur in 50%-60% of cases [39]. Nearly 20% of these infections progress to moderate-to-severe stages, frequently resulting in lower-limb amputations [39]. This condition severely impacts patient quality of life and imposes a substantial socioeconomic burden on healthcare systems.

The primary physiological characteristic of diabetic wounds is impaired healing. Prolonged hyperglycemia creates a complex microenvironment characterized by chronic inflammation, oxidative stress, impaired angiogenesis, and peripheral neuropathy, which are further exacerbated by persistent bacterial colonization [[39], [40], [41], [42]]. While conventional management, including systemic glycemic control, surgical debridement, and passive wound dressings, remains the standard of care, these approaches often fail to provide localized interventions capable of reversing the biochemical dysregulation at the wound site [39]. Consequently, there is a need for integrated therapeutic strategies that can simultaneously modulate multiple pathological factors.

In this context, MN technology has emerged as an effective platform for accelerating diabetic wound healing. Designed to address the specific biochemical characteristics of the diabetic microenvironment, advanced MNs have been engineered with integrated antibacterial, anti-inflammatory, antioxidant, and pro-angiogenic functionalities [[131], [132], [133]]. The primary advantage of MN platforms is their targeted delivery capability; by bypassing the SC to access deep dermal tissues, MNs facilitate the minimally invasive administration of concentrated therapeutic agents [[134], [135], [136], [137], [138]]. This approach ensures high localized drug concentrations while minimizing systemic side effects, providing a promising strategy for managing complex diabetic complications. The following sections review recent research advancements in diabetic wound therapy.

Diabetic Wound Management: From Intelligent Sensing to Microenvironment Remodeling.

The complex pathology of diabetic wounds, driven by persistent hyperglycemia, oxidative stress, and impaired vascularization, necessitates a transition from passive drug carriers to multifunctional therapeutic platforms. Early structural innovations focused on the spatiotemporal release of biochemical signals to address immediate clinical challenges. For instance, Guan et al. [133] and Liu et al. [134] demonstrated that compartmentalized MN architectures, utilizing substrates such as SilMA or Gel-CMC, could achieve the programmed release of antibacterial agents and growth factors (e.g., vascular endothelial growth factor (VEGF) and rh-EGF), effectively bridging acute infection control and chronic re-epithelialization (Fig. 9a). To further improve systemic regulation, Luo et al. [135] developed a wearable, sensor-controlled closed-loop system that couples real-time interstitial glucose sensing with ultrasonic-triggered insulin delivery through hollow PLA MNs, establishing a framework for autonomous diabetes management.

Fig. 9.

(a) Schematic presentation of the fabrication and application of MN-PBNs-VEGF patches for promoting diabetic wound healing [133].Reproduced with permission Copyright 2022 Small.(b) Schematic illustration of Fe₂C/GOx@MNs for eradicating MRSA biofilm from diabetic wound and preventing reinfection during wound healing [136]. Reproduced with permission Copyright 2023 Advanced Healthcare Materials. (c) Schematic illustration of composited microneedles promoting diabetic wound healing under Near-Infrared Light and Schematic illustration of the three major mechanisms by which composited microneedles promote diabetic wound healing by destroying bacterial biofilms, reducing the level of ROS, and promoting angiogenesis [137]. Reproduced with permission Copyright 2025 Nano Letters. (d) Schematic illustration of Fe₂C/GOx@MNs for eradicating MRSA biofilm from diabetic wound and preventing reinfection during wound healing [138]. Reproduced with permission Copyright 2023 Advanced Healthcare Materials.

Beyond glycemic control, the persistence of microbial biofilms remains a primary barrier to healing, prompting research into integrated treatment and prevention strategies. Sun et al. [136] engineered a nanozyme-based (Fe₂C/GOx) MN system that triggers a catalytic cascade to disrupt the extracellular polymeric substance (EPS) matrix while employing a chitosan backing layer to prevent secondary reinfection (Fig. 9b). This approach was further expanded by Wang et al. [137], who utilized NIR-responsive conjugated polymers to combine photothermal therapy with minocycline release (Fig. 9c). Additionally, Wu et al. [138] introduced a bacterial enzyme-responsive mechanism (Fig. 9d). By responding to hyaluronidase secreted by Staphylococcus aureus, their H/C@GO-AS@bFGF patch initiates a localized anti-biofilm defense, ensuring the stability of the antibacterial effect in complex polymicrobial environments.

As the understanding of chronic wound pathology has deepened, research has shifted toward the regulation of the oxidative-inflammatory-aging axis. Tian et al. [139] utilized CeO₂@Tau nanoparticles to mitigate cellular senescence (Fig. 10a), while He et al. [140] optimized this through a biphasic release system (V@MP/C@MN) that prioritizes ROS scavenging before promoting late-stage angiogenesis (Fig. 10b). To enhance catalytic efficiency, Xuan et al. [141] reported an amyloid-fibril-templated cerium oxide nanozyme with improved stability and cascade activity (Fig. 10c). These biochemical modulations are complemented by bioenergetic and gas therapies; for example, Cao et al. [142] introduced ultrasound-responsive CO-releasing MNs (Fig. 10d and e), and Gao et al. [143] utilized the photosynthesis of encapsulated Chlorella to resolve wound hypoxia via sustained oxygen generation (Fig. 10f).

Fig. 10.

(a) The multifunctional CTH@MN patch intricate mechanism for facilitating diabetic wound healing [139]. Reproduced with permission Copyright 2024 Small. (b) Schematic representation of V@MP/C@MN for diabetic ulcer repair [140]. Reproduced with permission Copyright 2024 Acta Biomaterialia. (c) Amyloid-templated ceria nanozyme reinforced microneedle for diabetic wounds treatment [141]. Reproduced with permission Copyright 2025 Advanced Materials. (d–e) Schematic illustration of the preparation of US-responsive MN@GOX@TiO_2-X@CO and their application in healing infected diabetic wound [142].Reproduced with permission Copyright 2025 Advanced Healthcare Materials.(f) A schematic diagram illustrating the synthesis of Chlorella-loaded PIL-based microneedles (PILMN-Chl) [143]. Reproduced with permission Copyright 2024 Advanced Materials.

Recent advancements in diabetic ulcer therapy involve the integration of regenerative medicine with exogenous physical stimuli. Xu et al. [144] and Zhang et al. [145] demonstrated the minimally invasive delivery of adipose-derived stem cells (ADSCs) (Fig. 11a and b) and MSC-exosomes (Fig. 11c and d), respectively, with the latter utilizing the Hofmeister effect to modulate the mechanical strength and release kinetics of hydrogel MNs. Expanding on physical-chemical synergy, Li et al. [146] and Zhang et al. [148] developed self-powered platforms that convert biomechanical or biochemical energy into bioelectrical stimulation, promoting neovascularization alongside targeted drug delivery (e.g., deferoxamine) (Fig. 11e). Furthermore, Ye et al. [147] introduced morphologically switchable gold nanowires that transform under ultrasonic guidance, enabling prolonged glucose decomposition and antioxidant action (Fig. 11f). Collectively, these studies illustrate a transition from single-target treatments toward systemic microenvironment remodeling, providing targeted solutions for diabetic chronic wounds.

Fig. 11.

(a) Schematic illustrations of the MN system loaded with ADSCs and PDGF-D and (b) Application of MNs for diabetic wound treatment [144]. Reproduced with permission Copyright 2023 Advanced Functional Materials. (c–d) Schematic illustration of the adaptive mechanical strengths and wound healing mechanisms of the indwelling microneedles [145]. Reproduced with permission Copyright 2023 Advanced Materials. (e) The schematic illustration for the design and preparation of the GDZ@mMNP-PENG for infected diabetic wound healing [146]. Reproduced with permission Copyright 2025 Chemical Engineering Journal. (f) Schematic illustration for the construction and therapeutic mechanisms of the ASHR MN-based wound healing strategy [147]. Reproduced with permission Copyright 2025 Advanced Materials.

The transition toward systemic microenvironment remodeling represents a promising direction; however, critical implementation gaps persist. The db/db mouse model, used in over 90% of the reviewed studies, exhibits substantially faster healing kinetics than human DFUs and lacks the peripheral neuropathy, macrovascular disease, and chronic hyperglycemia that define the clinical pathophysiology. Platforms demonstrating complete wound closure in 14-21 days may yield only marginal improvements in human trials that require 3-6 months for healing. Gas therapy and self-powered electrical stimulation face scalability challenges: maintaining viable Chlorella during shelf storage or ensuring consistent piezoelectric output across variable activity levels may limit their clinical utility. Importantly, none of the reviewed studies addressed recurrence prevention, which is a major clinical issue, as 40% of healed DFUs recur within 12 months.

Table 7 summarizes these advancements. However, MN platforms focusing exclusively on acute wound closure without modulating metabolic (hyperglycemia) and biomechanical (plantar pressure) drivers remain limited in their clinical applicability. The future of DFUs therapy requires moving beyond simple drug delivery toward comprehensive wound management. This involves integrating glucose-responsive biosensing with pressure-offloading mechanics to balance metabolic control and regenerative signaling. Addressing these factors is essential for translating these platforms into durable, point-of-care solutions.

Table 7.

Applications of microneedles in Diabetes.

MN Formulation/Designation	Material/Structure	Main Function	Limitations	References
MN-PBNs-VEGF	SilMA base, tips with PBNs and VEGF; base loaded with polymyxin B	Antioxidation, angiogenesis, antibacterial	Limited efficacy in complex infections	[133]
DMN@TH/rh-EGF	HA and Gel-CMC double-layer; TH and rh-EGF loading	Antibacterial, antioxidant, pro-angiogenic	Requires further microenvironment modulation	[134]
Wearable sensor-controlled ultrasound closed-loop system	Hollow PLA microneedles with glucose sensing and insulin delivery	Blood glucose detection and insulin control	No wound treatment, potential for integration	[135]
Fe2C/GOx@MNs	Fe2C and GOx-loaded microneedles; chitosan backing	Biofilm clearance, antibacterial	Further study on inflammation modulation needed	[136]
CPNM/F@MN	PVA base, HA tips with conjugated polymer and bFGF	Photothermal, antibacterial, angiogenesis	Biocompatibility and efficacy combined	[137]
H/C@GO-AS@bFGF	Hyaluronidase-degradable shell, core loaded with bFGF	Antibacterial, angiogenic, anti-inflammatory	Requires enhanced antibacterial spectrum and stability	[138]
CTH@MN	HA hydrogel with CeO2@Tau nanoparticles	Antioxidant, anti-inflammatory, anti-aging	Safety and broader wound applicability need evaluation	[139]
V@MP/C@MN	CONPs for ROS scavenging (base), VEGF (tips)	ROS scavenging, angiogenesis	Requires dose/time optimization	[140]
Lys-AFs-Ceria + GOX MN	Amyloid-fiber-assembled CeO2 nanozyme with GOX	Microenvironment modulation, catalysis	Scaling and clinical translation needed	[141]
MN@GOX@TiO2-x@CO	HA with GOX, TiO2-x, and CO donors	Gas therapy, antibacterial, fibroblast proliferation	Innovative gas-therapy MN strategy	[142]
PILMN-Chl	Polyionic liquids with Chlorella	Antibacterial, oxygenation	Chlorella viability and infection spectrum need research	[143]
ADSCs + PDGF-D MN	HAMA-based scaffold with ADSCs and PDGF-D	Stem cell therapy, angiogenesis	Needs improved viability and factor stability	[144]
MSC + MN@exo	PVA tip with MSC-exosomes; 3M tape base	Angiogenesis, wound healing	Needs stability and long-term biosafety data	[145]
GDZ@mMNP-PENG	PENG top layer, multifunctional MN base	Electric stimulation, antibacterial, angiogenesis, collagen synthesis	Innovative multi-modal treatment	[146]
ZGH-MN	ZIF-8 encapsulated GOx and HRP microneedles with electrodes	Hypoglycemic, antibacterial, anti-inflammatory, electrotherapy	Electrical stimulus requires optimization	[148]
Hb-RSV MN	Deformable gold nanowires and Hb-RSV nanoparticles	Anti-hypoxia, antioxidant, anti-inflammatory, glucose control	Innovative glycemic and wound control	[147]

2.3. Applications of MNs in oral ulcers

Oral aphthous ulcers are a prevalent mucosal condition that negatively affects patient quality of life, occurring in approximately 25% of the young adult population [149,150]. These lesions compromise mucosal barrier integrity, increasing the susceptibility of underlying tissues to microbial infiltration and secondary infections, particularly in immunocompromised patients [[151], [152], [153]]. Although topical antimicrobials are commonly used, the global increase in antimicrobial resistance (AMR) has limited their long-term clinical efficacy [[154], [155], [156], [157], [158], [159]].

The primary challenge in managing oral lesions is the dynamic physiological environment of the oral cavity. Unlike the skin, the oral mucosa is continuously exposed to salivary flow and masticatory movements [160]. Conventional treatments, such as mouthwashes or orodispersible tablets, are often ineffective due to rapid dilution or mechanical clearance within an hour [[161], [162], [163]]. This transient retention is insufficient to maintain the 12-24 h therapeutic window required for pathogen eradication or re-epithelialization [164]. Consequently, there is a clinical need for MN platforms capable of achieving prolonged localized retention.

The structural advantage of MNs is their ability to penetrate the epithelium and lamina propria, creating transient microchannels that protect therapeutic payloads from salivary degradation [[165], [166], [167], [168]]. Recent advancements have transitioned from basic drug loading to multi-functional intervention strategies. Early studies focused on rapid-dissolution kinetics to counteract saliva washout; for instance, Wang et al. [169] developed 3D-printed HA MNs that dissolve within 10 s to deliver a combination of dexamethasone, vitamin C, and tetracaine. Similarly, Guo et al. [170] utilized a 15x15 array for the dual-delivery of betamethasone, achieving enhanced fibroblast migration compared to commercial ointments (Fig. 12a and b).

Fig. 12.

(a) Schematic representation of the preparation of BSP-BDP@HAMNs and (b) their application in oral ulcers [170]. Reproduced with permission Copyright 2023 Colloids and Surfaces B: Biointerfaces. (c) Schematic illustration of the PIL-DS buccal tissue adhesive patch synthesis and its application in oral aphthous ulcers with bacterial infection [171].Reproduced with permission Copyright 2023 Acta Biomaterialia.(d) Schematic illustration of the transmucosal delivery of HAMA-HA-PVP MNs [172]. Reproduced with permission Copyright 2023 ACS Applied Materials & Interfaces. (e) Schematic presentation of the application of multifunctional HA/HACC composite microneedle patches for promoting oral ulcers healing [173]. Reproduced with permission Copyright 2023 Materials Today Bio. (f) Schematic diagram of gradual release of MNs for local oral anesthesia [174]^. Reproduced with permission Copyright. (g) Schematic depiction illustrating the utilization of HEMC MNs to promote oral ulcer healing [175]. Reproduced with permission Copyright 2024 Journal of Nanobiotechnology. (h) The design and fabrication of the NIR-responsive MXene-integrated microneedles to promote oral ulcer healing and (i) The application of the microneedles in the oral ulcer site [176]. Reproduced with permission Copyright 2025 Smart Medicine. (j) Preparation of MH/OPC-HP MNs and their application in promoting oral ulcer wound healing [177]. Reproduced with permission Copyright 2025 ACS Biomaterials Science & Engineering.

To ensure stability in the moist oral environment, research has focused on advanced bioadhesive and sequential-release architectures. Zhang et al. [171] addressed the infection-inflammation axis using a catechol-functionalized poly(ionic liquid) patch (PIL-DS), which exhibited a wet mucosal adhesion force of 16.2 kPa (Fig. 12c). For complex symptom management, Meng et al. [172] introduced a double-layer MN structure providing immediate lidocaine-mediated pain relief followed by sustained betamethasone release (Fig. 12d). This multi-functional approach is further demonstrated by the HA/HACC composite MNs developed by Zeng et al. [173], which integrate antibacterial and pro-angiogenic functions (Fig. 12e).

Beyond inflammation, MN technology has been applied to local anesthesia and natural product delivery. Li et al. [174] demonstrated a hydrogen-bonded adhesive MN array for lidocaine delivery that achieved seven times the efficiency of traditional creams (Fig. 12f). In parallel, Liu et al. [175] explored natural product therapy using magnesium-MOF MNs loaded with curcumin (Fig. 12g). Recent advancements have transitioned toward stimuli-responsive platforms that react to the specific pathological microenvironment of the oral cavity. Song et al. [176] developed an MXene-integrated hydrogel MN that utilizes NIR-triggered photothermal effects to accelerate dexamethasone release and exert direct thermal bactericidal action, achieving complete ulcer repair within 7 days (Fig. 12h and i). To address underlying oxidative stress, Zhang et al. [177] reported an ROS-responsive gel MN (MH/OPC-HP) capable of scavenging 85.1% of local ROS, thereby modulating the inflammatory microenvironment to accelerate wound closure (Fig. 12j). Furthermore, the application of MN technology has been extended to periodontal diseases. Li et al. [178] developed a minocycline-loaded dissolvable MN (Mino-DMN) that effectively targets periodontitis by reducing the gingival index and alveolar bone resorption. Collectively, these studies illustrate the clinical potential of MN arrays in providing targeted oral therapeutic solutions. Table 8 summarizes the applications of microneedles for oral ulcers.

Table 8.

Applications of microneedles in Oral Ulcers.

MN Formulation/Designation	Drugs	Structure	Main Functions	References
ROUMN	Dexamethasone Acetate (Dex), VC, Tetracaine Hydrochloride (TH)	3D printing + HA matrix	Pseudomembrane penetration; rapid dissolution; promotes cell viability.	[169]
BSP-BDP@HAMNs	BSP + BDP (two beclomethasone derivatives)	15×15 HA dissolving array	Synergistic anti-inflammatory; 3-min rapid dissolution; promotes fibroblast migration.	[170]
PIL-DS@MN	Diclofenac Sodium (DS)	Catechol-based ionic liquid polymer	Ultra-strong mucosal adhesion; high bactericidal rate; sustained anti-inflammatory effect.	[171]
HAMA-HA-PVP MNs	Beclomethasone + lidocaine	Bilayer (HAMA/HA) matrix	Sequential release: Immediate anesthesia followed by sustained anti-inflammation.	[172]
HA/HACC@DXMS, HA/HACC@bFGF	dexamethasone (DXMS) + bFGF; +antibacterial agents	HA/Quaternary ammonium chitosan	Rapid 2-min release; potent antibacterial action; promotes angiogenesis.	[173]
Lido-PVP/PVA DMNP	Lidocaine	Polyvinyl alcohol/chitosan (PVA/CS) + colloidal structure	5-minute rapid drug release, strong adhesion, excellent anesthetic effect	[174]
HEMC MNs	Curcumin (CUR)	Magnesium-MOF composite	Multimodal therapy: Long-term antioxidant, antibacterial, and anti-inflammatory effects.	[175]
MXene MN	Dexamethasone (Dex)	HA/Gelatin/MXene hybrid	NIR-activatable: Synergistic photothermal sterilization and accelerated drug release.	[176]
MH/OPC-HP MNs	Highly active antioxidant components	ROS-responsive matrix	Microenvironment-sensing: Triggers drug release and ROS scavenging at oxidative stress sites.	[177]
Mino-DMN	Minocycline (Mino)	Dissolving HA matrix	Periodontal protection: Rapid release (>80% in 5 min); inhibits alveolar bone resorption.	[178]

The development of stimuli-responsive and periodontal-specific systems represents significant progress; however, critical translational challenges remain. The rapid epithelial turnover (3-5 days) and strong healing capacity of the oral mucosa mean that many ulcers resolve spontaneously within 7-10 days, questioning the clinical necessity of complex MN platforms for routine aphthous ulcers, especially considering the cost difference compared to conventional corticosteroid mouthwashes. Wet mucosal adhesion (e.g., 16.2 kPa) also faces practical mechanical challenges, including masticatory shear forces (up to 150 N), salivary flow (0.3-0.5 mL/min), and pH fluctuations (6.2-7.8), which static bench assays fail to capture. The reported prolonged residence times may not be maintained under actual masticatory stress. Furthermore, periodontal applications (e.g., Mino-DMN) present an anatomical mismatch, as periodontal pockets are deep, narrow sulci that are inaccessible to standard MN arrays without specialized insertion devices, a constraint not addressed in the reviewed studies.

Future translation into routine dental practice requires strategic prioritization rather than broad indication expansion. Rather than competing with inexpensive first-line options for minor ulcers, oral MN platforms should target specific clinical needs where conventional modalities are insufficient, such as refractory major aphthous ulcers (>1 cm, >6 weeks) in immunocompromised patients and post-surgical mucosal defects requiring sustained drug delivery. Within these applications, the focus should shift toward integrating diagnostic capabilities with adhesive platforms that withstand masticatory stress and provide real-time feedback. This approach ensures that material resilience aligns with oral biomechanics rather than simply adapting cutaneous MN designs.

2.4. Applications of MNs in cancer therapy

MN arrays provide a localized alternative to traditional systemic administration, which is often limited by poor pharmacokinetics and off-target toxicity [31,32]. By physically penetrating biological barriers such as the SC or dense tumor stroma, MN platforms facilitate direct drug delivery into the tumor microenvironment [33,179]. This localized distribution helps overcome physiological barriers like elevated interstitial pressure, thereby enhancing the therapeutic index of chemotherapeutics while minimizing accumulation in healthy tissues and reducing adverse side effects [[34], [35], [36]].

For glioblastoma multiforme (GBM), the blood-brain barrier (BBB) and chemoresistance remain major clinical challenges. To address this, Yang et al. [180] developed a 3D laser-printed MN array (HMNs@TMZ/siPLCG1) for the concurrent delivery of temozolomide (TMZ) and PLCG1-siRNA. By downregulating the PLCG1/STAT3 axis, this platform sensitizes GBM cells to alkylating agents, extending survival in orthotopic models. The same group also developed an albumin-based system (BMNs) that sustains the release of TMZ and niclosamide for over 28 days to inhibit recurrent tumor growth (Fig. 13a) [181]. In addition, recent intracranial therapies have focused on postoperative recurrence management. Zhang et al. [182] used biodegradable MNs to deliver immune nanostimulants (GMANs) into resection cavities, polarizing tumor-associated macrophages toward a pro-inflammatory phenotype to eliminate residual malignant cells (Fig. 13b). Furthermore, Jiang et al. [183] integrated acid/light-activated PROTAC nanoparticles with self-oxygenating BSA-MnO₂ (PPT7/BM) to facilitate BBB penetration and alleviate hypoxia, thereby improving the efficacy of photodynamic therapy (PDT) and targeted protein degradation (Fig. 13c).

Fig. 13.

(a) Schematic representation of BMNs@TMZ/NIC fabrication for in situ synergistic treatment of GBM (Glioblastoma) [181].Reproduced with permission Copyright 2024 ACS Applied Materials & Interfaces. (b) The application of GMAN@CMN in GBM treatment [182]. Reproduced with permission Copyright 2024 Advanced Materials. (c) Self-oxygenating PROTAC microneedle platform for in situ protein degradation and potentiated therapy of GBM [183]. Reproduced with permission Copyright 2025 Advanced Materials. (d) Schematic of the grooved microneedle patch [184]. Reproduced with permission Copyright 2024 Advanced Materials. (e) Schematic illustration of a microwave-responsive engineered platelet prepared using magnetic biometa [179]. Reproduced with permission Copyright 2025 ACS Applied Materials & Interfaces. (f) Schematics of the bioinspired adhesive and drug-integrated microneedle patch and its application for treating pancreatic cancer [185]. Reproduced with permission Copyright 2022 Chemical Engineering Journal.

Beyond the central nervous system, MN technology has been applied to improve adoptive T cell therapy (ACT) and energy-driven interventions in solid tumors. Zhou et al. [184] developed a CCL22-modified grooved MN patch to modulate the tumor microenvironment, recruiting effector T cells while excluding immunosuppressive regulatory T cells (Fig. 13d). For microwave-enhanced therapy, Liu et al. [179] integrated engineered platelets with Fe₃O₄@MOF nanomedicine into a microwave-responsive MN system, using localized hyperthermia to promote drug penetration (Fig. 13e). In pancreatic cancer, Fu et al. [185] designed a highly adhesive GelMA MN array for efficient gemcitabine delivery (Fig. 13f), while Shao et al. [186] developed a self-heating multi-stage MN array for skin cancer to optimize drug release under varying conditions (Fig. 14a).

Fig. 14.

(a) Schematic illustration of the self-heating MN patch [186]. Reproduced with permission Copyright2024 Advanced Materials. (b) Schematic illustration of sustained release of nano-complexes containing pOVA and Poly(I/C) into professional APCs from bMNs [187]. Reproduced with permission Copyright 2023 Biomacromolecules. (c) Schematic diagram of metronomic photodynamic tumor therapy based on microneedles and AIE photosensitizers [188].Reproduced with permission Copyright 2023 ACS Applied Materials & Interfaces. (d) Schematic of the MN system for synergetic cancer therapy [189]. Reproduced with permission Copyright 2021 ACS Applied Materials & Interfaces. (e) Design and fabrication of the MN-mediated EDT sensing and treatment integrated microneedle system [190]. Reproduced with permission Copyright 2025 Nano Today. (f) Schematic illustration of wf-UMP application for cancer therapy [191]. Reproduced with permission Copyright 2025 Nature Communications. (g–h) Schematic illustration of US-activated pyroptosis-driven immunotherapy mediated by a silk-based MN patch [192]. Reproduced with permission .Copyright 2026 Nano Today.

Recent studies have also explored the integration of immunotherapy and real-time diagnostics. Duong et al. [187] constructed biodegradable copolymer MNs (bMNs) for the sustained delivery of agents to inhibit lung metastasis (Fig. 14b). Cheng et al. [193] demonstrated continuous PROTAC delivery via pH-sensitive micelles embedded in MNs to degrade estrogen receptors in breast cancer. In phototherapy, Dai et al. [188] incorporated AIE photosensitizers into MNs to enhance rhythmic photodynamic therapy (mPDT) under low-intensity illumination (Fig. 14c). He et al. [189] combined hyaluronidase-modified semiconductor nanoparticles with immunoadjuvants in dissolving MNs to overcome the melanoma stromal barrier and elicit an immune response (Fig. 14d).

Furthermore, Xie et al. [190] developed a metal MN array integrating drug delivery, electrical stimulation, and real-time ROS sensing for tumor electrotherapy (Fig. 14e). Simulations showed enhanced cytotoxic ROS generation and apoptosis induction compared to conventional electrodes, effectively killing triple-negative breast cancer cells while activating immune responses, although its application is currently limited to superficial tumors. Xue et al. [191] developed a wearable flexible ultrasonic MN patch (wf-UMP) combining piezoelectric nanoparticles with a bio-adhesive hydrogel (Fig. 14f). This system inhibits tumor growth and synergizes with anti-PD1 to induce systemic immune memory. Similarly, Zhang et al. [192] used an ultrasound-responsive silk fibroin MN patch (CuT-MN) encapsulating Cu-TCPP MOF nanosheets to induce immunogenic cell death via ultrasound-triggered ROS propagation (Fig. 14g and h). This approach drives immune reversion and synergizes with anti-PD-1 blockade for systemic anti-tumor immunity.

The transition from localized ablation to systemic anti-tumor immunity represents significant progress; however, several translational challenges remain. GBM studies typically use orthotopic xenografts in immunodeficient mice, which cannot accurately model the interactions between MN-delivered immunostimulants and intact host immunity. This makes the efficacy of cGAS-STING activation and CAR-T recruitment strategies difficult to predict in immunocompetent patients. Additionally, there is often a confusion between transdermal and intratumoral delivery in solid tumor applications. MNs typically penetrate 200-1000 μm, whereas pancreatic tumors and deep melanoma metastases are located at much greater depths. For instance, adhesive MNs designed for pancreatic cancer cannot reach the retroperitoneal pancreas without surgical implantation. Furthermore, integrating real-time ROS sensing and electrical stimulation introduces regulatory complexity related to active medical device classification, which may delay clinical translation.

Table 9 summarizes these advancements. Rather than focusing on deep-tissue applications, we suggest that MN-mediated oncology should prioritize its primary advantage: the minimally invasive management of superficial malignancies and cutaneous metastases, such as melanoma in-transit metastases and breast cancer chest wall recurrences. In these cases, transdermal access is anatomically appropriate and can maximize quality-of-life benefits. Achieving clinical success in this area requires addressing the long-term biosafety of electronic components and standardizing multi-layered sterile manufacturing, ensuring that these interventions provide durable survival benefits while overcoming the anatomical and regulatory challenges mentioned above.

Table 9.

Applications of microneedles in Cancers.

Target Cancer	MN Formulation/Designation	Drugs	Structure and Materials	Functions	References
Glioblastoma (GBM)	HMNs@TMZ/siPLCG1	Temozolomide (TMZ) + PLCG1 - siRNA	3D laser printing + PDMS replica molding	Sensitizes GBM to chemo by downregulating PLCG1/STAT3 axis.	[180]
Drug-resistant GBM	BMNs@TMZ/NIC	Niclosamide (NIC) + TMZ	BSA + HA for increased viscosity, spatiotemporal drug release,	Spatiotemporal controlled release (>28 days) to overcome resistance	[181]
Postoperative GBM	GMAN@CMN	GMANs (OBNs + anti-Siglec10 antibody)	Implantable microneedles + immune nanostimulants	Activates tumor-associated macrophages to inhibit recurrence.	[182]
GBM	PROTAC/BSA - MnO2	PPT7 NPs + BSA - MnO2	Dual - responsive structure (acid + light), self - oxygenating nanoparticles	Bypasses BBB and alleviates hypoxia for enhanced PDT.	[183]
Solid Tumors	CAR-T@MNs-CCL22	/	Ice-templated microneedles, polydopamine modification, gelatin hydrogel for T cells	Recruits effector T cells and reduces Treg infiltration (ACT enhancement).	[184]
Solid Tumors	Fe3O4@MOF	Fe3O4@MOF	Engineered platelets + microwave - thermal nanomedicine	Localized hyperthermia to promote deep drug penetration.	[179]
Pancreatic Cancer	Bioinspired adhesive GelMA MN patch	Gemcitabine (GEM)	Adhesive GelMA (octopus-mimicked microstructure)	Strong adhesion, stroma penetration, sustained local release	[185]
Lung Metastasis (Prevention)	PEG−PSMEU	/	PEG + PSMEU copolymer, slow degradation at injection site	Sustained systemic delivery to inhibit metastatic seeding.	[187]
ER + Tumors	MPEG-PAE	PROTAC + CDK4/6 Inhibitor	pH - sensitive MPEG - PAE micelles + biodegradable microneedles	Continuous delivery of PROTACs to degrade estrogen receptors.	[193]
Cancer Photodynamic Therapy	Microneedles@AIE PSs	Aggregation - Induced Emission (AIE) Photosensitizer	Microneedle device + wireless LED light source	Enhances rhythmic PDT (mPDT) under low-intensity light.	[188]
Triple-Negative Breast Cancer	DON@Pd-Pt NPs/MN	/	Metal array + real-time ROS sensing + COMSOL simulation	Integrates delivery, electrical stimulation, and ROS sensing.	[190]
Solid Tumors	wf - UMP	Anti-PD1 + Piezoelectric Nanoparticles	Flexible wf-UMP patch	Induces immune memory and piezo-catalytic therapy.	[191]
Solid Tumors	US-responsive CuT-MN	2D Cu-TCPP MOF nanosheets + anti-PD-1	Silk fibroin matrix + 2D MOF nanosheets	Ultrasound-triggered ROS drives GSDME pyroptosis; reverses “cold” TME to enhance immunotherapy	[192]

2.5. Applications of MNs in ocular diseases

Ocular drug delivery presents significant pharmacological challenges, primarily due to the corneal epithelial barrier and rapid lacrimal turnover, which limit the bioavailability of conventional topical formulations. To improve the delivery of hydrophobic agents such as cyclosporine A (CsA), Alrbyawi et al. utilized dissolvable PVP-based MN arrays (8×8), demonstrating higher drug concentrations in the posterior segment compared to standard emulsions [194]. To minimize tissue trauma during ocular intervention, Wang et al. [195] engineered an annular corneal microneedle (A-MN) patch composed of PVP-β-CD and PVA (Fig. 15a). This geometry avoids central corneal puncture, effectively delivering levofloxacin to the stroma and anterior chamber while preserving nerve density and visual axis integrity, which is important for managing infectious keratitis in elderly patients.

Fig. 15.

(a) Schematic illustration of annular microneedle (A-MN) in treating corneal diseases [195]. Reproduced with permission Copyright 2025 Science Advances. (b) Simplified schematic diagram illustrating the application of MNs in customized CXL [196]. Reproduced with permission Copyright 2024 Advanced Materials. (c) Schematic illustration of the fabrication process and therapeutic mechanism of the ROS-responsive separable MN patches for SSDE therapy [197]. Reproduced with permission Copyright 2025 Advanced Science. (d) Schematic illustration depicting the application process of the microneedle patch [198]. Reproduced with permission Copyright 2025 Advanced Science. (e) Schematic illustration of the composite MNs for IVDD [199].Reproduced with permission Copyright 2024 Advanced Materials. (f) Preparation of T-MN@EXO@miR-378 and engineered exosomes and (g) T-MN@EXO@miR-378 sustainably release exosomes and regulate ECM and mitophagy [28]. Reproduced with permission Copyright 2024 Bioactive Materials. (h–i) Self-powered triboelectric-responsive EXPLOR engineered EV release for biologically targeted IVDD treatment via optically reversible protein-protein interactions [200]. Reproduced with permission Copyright 2024 Nature Communications. (j) Flow chart for preparing ROS-responsive particles co-loading betamethasone and ropivacaine as well as thermosensitive therapeutic hydrogel and (k) Working mechanism of therapeutic hydrogel in alleviating pain and inflammation in symptomatic LDH [201]. Reproduced with permission Copyright 2024 Advanced Healthcare Materials. (l) Diagram of the Mechanism by which efferocytosis of CAR-eM mediates intervertebral disc repair [202]. Reproduced with permission Copyright 2025 Cell Reports Medicine.

Recent studies have focused on integrating MNs with established clinical protocols to improve therapeutic efficiency. For example, in the management of keratoconus (KC), Yang et al. [196] combined MN-mediated riboflavin delivery with corneal cross-linking (CXL) technology (Fig. 15b). This approach facilitates rapid epithelial penetration and achieves biomechanical reinforcement equivalent to traditional debridement-based protocols within 20 min, while reducing procedural trauma. Similarly, to improve the permeability of antifungals in fungal keratitis (FK), Shi et al. [203] optimized PLA/HA dissolvable MNs that provide reversible penetration and prolonged residence in the conjunctival sac, achieving efficacy comparable to invasive intrastromal injections.

Recent ophthalmic MN research has focused on stimuli-responsive systems adapted to the localized ocular microenvironment. For Sjögren's syndrome-related dry eye (SSDE), Mu et al. [197] developed a separable, ROS-responsive MN patch (CE-MN). By responding to the oxidative stress characteristic of inflamed lacrimal glands, the system triggers the release of CsA and EGCG, restoring tear secretion and goblet cell density (Fig. 15c). For meibomian gland dysfunction (MGD), Yu et al. [198] reported a photothermal-responsive patch incorporating an IR820 derivative (Fig. 15d). Under NIR light, this system triggers the release of rosiglitazone (a PPAR-γ agonist), achieving deeper penetration into the eyelid skin than oral administration. Table 10 summarizes the applications of MNs in the management of ocular diseases.

Table 10.

Applications of microneedles in Eyes.

Specific MN System	Drug	Function	Limitations	References
CsA + PVP-MN	Cyclosporine A (CsA)	Enhanced drug solubility and release; improved delivery to the posterior eye segment	Long-term safety of ophthalmic microneedles needs study	[194]
A-MN	Levofloxacin (LVFX)	Avoids corneal center; delivers to stroma & anterior chamber; improves bioavailability; reduces tissue & nerve damage	Requires clinical validation for long-term efficacy and safety	[195]
RF + UVA/MN	Riboflavin (RF)	Trans-epithelial RF delivery; UVA strengthens corneal biomechanics; reduces epithelial trauma	Needs optimization for long-term safety and effectiveness	[196]
PLA-HA MN	/	Penetrates corneal epithelium; extends drug retention in conjunctival sac; boosts bioavailability	Mass production & storage stability need improvement	[203]
CE-MN	Cyclosporine A (CsA) + EGCG	Accelerated ROS-triggered drug release; antioxidant & anti-inflammatory; low cytotoxicity; targeted lacrimal delivery	Requires further optimization for clinical use	[197]
ROSI-MN	Rosiglitazone (ROSI)	NIR-triggered heating & drug release; PPAR-γ activation; penetrates eyelid skin for localized treatment	Long-term safety & multi-etiology effectiveness need further study	[198]

Although MN technology addresses the challenge of poor posterior segment bioavailability in ophthalmic diseases, there is a gap between current engineering designs and ocular anatomical realities. Most pharmacokinetic studies report corneal drug levels without establishing therapeutic thresholds or correlating with clinical efficacy endpoints, such as visual acuity improvement. While annular MN designs avoid central puncture, the long-term consequences of repeated paracentral micropunctures, including iatrogenic astigmatism, stromal haze, and Descemet's membrane damage, remain uncharacterized. Given the limited regenerative capacity of the cornea in elderly patients, these safety data are essential. Patient self-administration also faces practical constraints. Ocular insertion requires precise visual axis alignment, sterile technique, and tolerance of transient visual obstruction, which may exceed the dexterity of elderly patients, who are the primary demographic for infectious keratitis and dry eye disease.

In conclusion, these studies demonstrate the potential of MNs for treating dry eye, keratoconus, infectious keratitis, and meibomian gland dysfunction. However, rather than pursuing chronic self-administration, ocular MN platforms should prioritize intraoperative applications, such as sustained drug release following corneal cross-linking or cataract surgery, to utilize the controlled operating environment and mitigate safety risks. Within this framework, enhancing mechanical compliance and curvature adaptability to match corneal topography, developing biodegradable ultra-transparent matrices, and rigorously evaluating long-term biosafety (e.g., corneal nerve density and intraocular pressure) remain essential. The integration of nanomedicine and smart polymers may establish MN platforms as a key approach in next-generation ophthalmology, provided that clinical translation focuses on intraoperative rather than chronic self-administration applications.

2.6. Applications of MNs in musculoskeletal and orthopedic disorders

Musculoskeletal and orthopedic pathologies, including intervertebral disc degeneration (IVDD), spinal cord injury (SCI), osteoarthritis (OA), and osteoporosis, are a leading cause of global disability, characterized by persistent inflammation and progressive ECM degradation [204]. The unique structural characteristics of these tissues, particularly the avascular nature of the nucleus pulposus and the restricted access to joint cavities, often limit the efficacy of systemic pharmacology. To overcome these challenges, MN technology has been developed as a minimally invasive approach capable of bypassing anatomical barriers to achieve targeted intervention in avascular niches or the systemic circulation with high precision.

The development of spinal therapies reflects a transition from passive scaffolds to regenerative, microenvironment-adaptive systems. Initial research focused on mitigating inflammatory cascades within the disc; for example, Wang et al. [204] utilized a Cur-SLNs/GelMA hydrogel to restore ECM homeostasis, while Meng et al. [199] engineered high-strength PDA/GelMA MNs to combine photothermal therapy (PTT) with localized diclofenac release (Fig. 15e). However, addressing underlying cellular dysfunction requires more specific molecular interventions. Hu et al. [28] developed thread-structured SilMA MNs to facilitate the recovery of impaired mitophagy in the annulus fibrosus (Fig. 15f and g). This progression toward responsive interventions is further demonstrated by the self-powered, triboelectric-responsive device reported by Zhang et al. [200], which converts mechanical energy from movement into a trigger for the release of optogenetically engineered extracellular vesicles (EVs), coupling mechanical sensing with biological repair (Fig. 15h and i).

Recent advancements in neural and degenerative spinal care have integrated advanced cell therapies and nanotechnology. For SCI management, Qian et al. [205] developed RHNP-Cur nanoparticles to attenuate secondary injury cascades, while Deng et al. [201] addressed the severe pain associated with lumbar disc herniation using an in situ forming hydrogel for the sustained co-delivery of betamethasone and ropivacaine (Fig. 15j and k). Notably, recent IVDD research has focused on engineered cell delivery; Zhou et al. [202] developed a specialized MN platform for CAR-M-like engineered macrophages (CAR-eMs), which restore disc homeostasis by enhancing efferocytosis within the degenerated stroma (Fig. 15l).

Beyond the axial skeleton, MN technology is advancing the management of peripheral joint diseases and systemic bone loss. In muscle injury models, Zhu et al. [206] utilized a photothermal-responsive hydrogel patch (TPH@MN) that responds to the acidic microenvironment of chronic inflammation to accelerate tissue repair (Fig. 16a). For osteoarthritis (OA), Li et al. [207] integrated antioxidant PDA nanoparticles with MSC-derived exosomes to inhibit chondrocyte apoptosis via the PI3K-Akt-mTOR axis (Fig. 16b). Furthermore, MNs have shown significant potential for systemic disorders such as osteoporosis. By bypassing the hepatic first-pass effect, Yang et al. [208] increased the bioavailability of minodronic acid by 25.8 times, while Xu et al. [209] introduced a core-shell MN architecture (ALF-DCSMN) to extend the dosing interval of alfacalcidol from daily to bi-weekly through a sustained intradermal reservoir. The applications of microneedles in lumbar and orthopedic diseases are summarized in Table 11, Table 12, respectively.

Fig. 16.

(a) Photothermal TPH@MN MN arrays promote healing of sTIs through anti-inflammaging modulation [206]. Reproduced with permission Copyright 2024 Small Structures. (b) Schematic depicting PDA@Exo MN-mediated modulation of cartilage degradation inhibition, osteogenesis enhancement, and macrophage polarization via the PI3K-AKT-mTOR signaling pathway [207]. Reproduced with permission Copyright 2024 Advanced Science.

Table 11.

Applications of microneedles in lumbar diseases.

Specific MN System	Key Components	Mechanism of Action	Limitations	References
Cur - SLNs/GelMA	Curcumin - loaded solid lipid nanoparticles	Regulates ECM metabolism and the immune microenvironment via anti-inflammatory effects.	NF-κB signaling pathways and clinical translatability require further study.	[204]
DCs + PDA/GelMA	Diclofenac sodium (DCs)	Synergizes photothermal therapy (PTT) with anti-inflammatory drug release to remodel the niche.	Limited NIR penetration depth; long-term therapeutic stability needs validation.	[199]
T -MN@EXO@ miR - 378	Engineered exosomes + miR - 378	Targets mitophagy regulation via sustained exosomal delivery for long-acting therapy.	Lack of biomechanical testing; efficacy in large animal models remains unproven.	[28]
EXPLOR-TENG	Optogenetically extracellular vesicles (EVs)	Mechanical-to-electrical conversion triggers drug release; specifically targets exercise-induced IVDD.	Long-term safety and effectiveness need further evaluation	[200]
RHNP - Cur	Curcumin-encapsulated nanoparticles	Adapts to the inflammatory microenvironment to inhibit the localized inflammatory cascade.	Requires optimization and evaluation before practical application	[205]
HTB/R@Gel	Betamethasone + Ropivacaine	In-situ gelation for sustained anti-inflammation and long-acting analgesia (pain relief).	Clinical dosage and degradation profiles in the spinal niche need further refinement.	[201]
CAR-eMs MN	CAR - M − like macrophages (CAR - eMs)	Enhances efferocytosis to clear apoptotic cells and restore disc homeostatic environment.	Long-term cell viability and efficacy in higher-order species are still unclear.	[202]

Table 12.

Applications of microneedles in Orthopedic Diseases.

Disease Type	Specific MN System	Key Components	Mechanisms of Action	References
Soft Tissue Injuries	TPH@MN	Taurine - Prussian blueNPs	pH/NIR-responsive ROS scavenging; inhibits SASP; induces M2 macrophage polarization.	[206]
Osteoarthritis (OA)	PDA@Exo MN	Polydopamine + stem cell exosomes	Activates PI3K-Akt-mTOR pathway; enhances ECM synthesis and inhibits chondrocyte apoptosis.	[207]
Osteoporosis	MA - MNs	Minodronic acid (MA)	Bypasses first-pass effect; achieves 25.8-fold higher bioavailability than oral delivery.	[208]
Osteoporosis	ALF - DCSMN	Alfacalcidol, Core-shell microparticles	Core-shell controlled release; eliminates burst release to enable 14-day sustained delivery.	[209]

The application of MN technology to musculoskeletal diseases represents a significant spatial expansion for the field; however, fundamental biomechanical and anatomical constraints require careful consideration. The intervertebral disc presents a complex delivery challenge, as the nucleus pulposus is avascular, under high osmotic pressure, and separated from the skin by multiple tissue layers. MN platforms cannot traverse these barriers without surgical implantation, making the term “transdermal IVD delivery” inaccurate, as it effectively requires minimally invasive surgery. The self-powered TENG-MN system, while innovative, requires percutaneous insertion into the annulus fibrosus, a procedure comparable in invasiveness to standard intradiscal injections. Furthermore, while MN-mediated osteoporosis therapy achieves significant bioavailability improvements (e.g., a 25.8-fold increase for minodronic acid), bisphosphonates already achieve near-complete bone resorption inhibition at standard oral doses. This marginal gain may not justify the manufacturing complexity compared to annual intravenous zoledronate administration. Additionally, mechanosensitive MNs for joint diseases assume predictable physiological loading patterns, whereas real-world joint loading is highly variable, which risks under-dosing or overdosing.

In conclusion, recent studies demonstrate substantial progress in orthopedic management. However, rather than pursuing chronic disease management where anatomical barriers and dosing precision requirements exceed current MN capabilities, we propose that orthopedic applications should focus on perioperative local drug delivery, such as post-arthroscopy anti-inflammatory depots and antimicrobial prophylaxis at spinal fusion sites, where the technology's strengths align with clinical needs. Within this framework, enhancing structural robustness for high-dynamic environments and establishing standardized manufacturing protocols remain essential. Ultimately, the integration of bioengineering and wearable electronics may establish MN platforms as a valuable approach in next-generation orthopedics, provided that clinical translation focuses on perioperative rather than chronic ambulatory applications.

2.7. Applications of MNs in cardiovascular diseases

Cardiovascular diseases, particularly myocardial infarction (MI), remain a leading cause of global morbidity and mortality. Conventional treatments for ischemic cardiomyopathy face significant limitations, prompting the exploration of MN technology as a targeted therapeutic approach. Recent studies have investigated MN applications in MI and related cardiovascular conditions from multiple perspectives, collectively advancing the development of this field.

The efficacy of conventional intramyocardial injection for ischemic cardiomyopathy is often limited by poor drug retention, localized tissue trauma, and embolic risks, necessitating the development of MN platforms for stable cardiac intervention. Shi et al. [29] engineered phase-change MNs loaded with adeno-associated virus (AAV) for targeted gene therapy (Fig. 17a–c). This platform demonstrated effective mechanical penetration and swelling-triggered release, successfully transfecting cardiomyocytes with VEGF to reduce infarct size and activate regenerative signaling in rat models. To provide a minimally invasive alternative to direct injection, Hu et al. [210] developed a detachable MN array composed of PLGA nanoparticles and an elastin-like polypeptide (ELP) gel (Fig. 17d). By delivering mesenchymal stromal cell factors (MSCF) directly to the epicardium, this system promoted cardiomyocyte proliferation and mitigated adverse cardiac remodeling, offering an effective approach to alleviate post-infarction fibrosis.

Fig. 17.

(a) Schematic hearts were administered MN-AAV with the assistance of a customized apparatus and (b) Diagram of our practice for the application of the MNs to rat heart via endoscopy-assisted microthoracotomy surgery and (c) A series of endoscopic images demonstrating the application of MNs for delivery of therapeutic agents to a rat heart [29].Reproduced with permission Copyright 2022 Science Advances. (d) Schematic diagram of the action mechanism and research progress of the detachable,microneedle patch for myocardial infarction treatment [210]. Reproduced with permission Copyright 2022 ACS Nano. (e) Schematic illustration of a MN array loaded with exosomes containing miR-29b mimics for MI treatment [211]. Reproduced with permission Copyright 2023 Advanced Healthcare Materials. (f) Schematic diagram of sequential drug release therapy for myocardial infarction with MNP [212]. Reproduced with permission Copyright 2025 Acta Biomaterialia. (g) Schematic showing the overall study design of the secondary drug-loaded MN patch [213]. Reproduced with permission Copyright 2025 Advanced Materials.

Subsequent research has focused on modulating the post-infarction microenvironment, with the delivery of exosomes and non-coding RNAs becoming a key area in anti-fibrotic therapy. Yuan et al. [211] developed a biocompatible gelatin-based MN array for the electroporation-assisted loading of miR-29b mimics (Fig. 17e). This system internalizes into cardiac fibroblasts, downregulating fibrosis-related proteins and suppressing the pathological transformation of the extracellular matrix. To optimize the therapeutic window of acute myocardial infarction (AMI), He et al. [212] introduced a microcapped MN array (MNPSustain) for the sequential delivery of methylprednisolone, IL-10, and VEGF (Fig. 17f). This programmable release profile aligns with the physiological stages of cardiac repair, initially suppressing inflammation before promoting angiogenesis, thereby maximizing functional recovery and minimizing myocardial hypertrophy.

Recent advancements in cardiac MN technology have integrated microenvironment sensing and responsive materials. Wang et al. [213] developed a dual-layered patch featuring an outer layer for pH regulation and an inner layer equipped with self-driven micro-robots for exosomes delivery (Fig. 17g). This system actively neutralizes the acidic microenvironment of ischemic tissues, enhancing the survival of regenerated cardiomyocytes and promoting vascular network formation. Validated in rabbit and porcine models, this platform demonstrates a transition from passive drug reservoirs to environment-adaptive systems. Collectively, these studies illustrate the progression toward high-precision, minimally invasive cardiac regeneration. The applications of MNs in cardiovascular diseases are summarized in Table 13.

Table 13.

Applications of microneedles in Cardiovascular Diseases.

Specific MN System	Key Components	Mechanism of Action	References
MN-AAV-VEGF	AAV + VEGF	Ensures high AAV retention; promotes endothelial cell migration and activates pro-angiogenic pathways.	[29]
MN - MSCF - NP	Mesenchymal stromal cell factor (MSCF) NPs	Facilitates selective cardiomyocyte uptake; promotes cell proliferation while inhibiting apoptosis.	[210]
MN + Exo/miR-29b mimic	Exosomes, miR-29b mimics	Suppresses fibroblast activation and pro-fibrotic protein expression; mitigates post-MI inflammation.	[211]
MNPSustain	Methylprednisolone (Mp), IL-10, VEGF	Sequential delivery of anti-inflammatory and angiogenic cues to synchronize myocardial repair.	[212]
Double - layer smart microneedle patch with micro - robots	Outer: VEGF nanoparticles; Inner: Exosome - loaded micro - robots	pH-responsive micro-robots regulate the acidic post-MI niche; enhance targeted exosome delivery and survival.	[213]

Although these cardiac MN platforms demonstrate significant bioengineering progress, they face substantial translational constraints. The rhythmic contractions of the myocardium (60-100 beats/min, intraventricular pressures 80-120 mmHg) create a biomechanical environment that challenges the static adhesion assumptions of current MN designs. For instance, detachable patches lack retention data under continuous cardiac motion; micromotion-induced shear stress may dislodge adhesive interfaces within hours or days, which is insufficient for the weeks required for therapeutic efficacy. Furthermore, micro-robotic patches assume a stable acidic post-MI niche, whereas ischemic myocardium exhibits rapid pH fluctuations during reperfusion and inflammatory resolution, potentially destabilizing pH-triggered release kinetics. Critically, the regulatory pathway for cardiac MN devices incorporating active robotics or gene therapy vectors remains undefined. Unlike cutaneous MNs (Class II), cardiac implants with gene delivery likely require Class III premarket approval (PMA), a regulatory burden that is difficult for academic groups to navigate independently.

In summary, cardiac MN technology offers a promising approach for ischemic cardiomyopathy and acute myocardial infarction. However, to overcome translational barriers, the field requires strategic partnerships with established cardiac device manufacturers early in the development process. Within this collaborative framework, research priorities should shift toward regulatory-compliant designs, such as bio-elastic adhesives validated under continuous rhythmic contractions and closed-loop architectures integrating diagnostic sensors with therapeutic release. Ultimately, establishing MN platforms as a viable clinical tool in cardiology depends on aligning material innovation with practical regulatory and manufacturing strategies.

2.8. Applications of MNs in neurological diseases

The clinical management of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is limited by the blood-brain barrier (BBB), which restricts the cerebral bioavailability of therapeutic agents. To address this challenge, Permana et al. developed a combinatorial transdermal strategy utilizing the trigeminal nerve pathway. By integrating polymer microneedles with a thermosensitive in situ gel loaded with rivastigmine-encapsulating solid lipid nanoparticles (SLN-RV-TG) [214], this platform achieved skin-temperature-triggered gelation and efficient stratum corneum penetration. In vivo rodent models demonstrated enhanced brain distribution and improved pharmacokinetic profiles compared to traditional routes, providing a minimally invasive alternative for AD therapy.

In addition to transdermal approaches, the nose-to-brain axis offers a direct pathway to bypass the BBB, although its efficacy is often limited by nasal mucociliary clearance. Ruan et al. [30] addressed this by developing a toothbrush-shaped dissolving MN system (Fig. 18a). Utilizing a hyaluronic acid matrix and a tannic-acid-crosslinked gelatin base, this system facilitates the rapid mucosal penetration of cyclodextrin-based metal-organic frameworks (CD-MOFs) loaded with huperzine A. This MN-mediated delivery improved memory impairment and attenuated neuronal damage in AD rats, demonstrating superior mucosal retention and targeted brain enrichment compared to conventional nasal drops.

Fig. 18.

(a) Schematic diagram of the mechanism of Nose-to-Brain targeted microneedle system for treating AD [30]^. Reproduced with permission Copyright 2024 Journal of Controlled Release. (b) Schematic of MFeI MNs microneedle preparation and mechanism for treating parkinson's disease [215]. Reproduced with permission Copyright 2024 Journal of Nanobiotechnology. (c) Intestinal peristalsis-actuated porcupinefish-inspired microneedle robots for oral delivery of biologic drugs [216]. Reproduced with permission Copyright 2024 Science Advances. (d) Schematic illustration of the application of the dual-electrostimulation E-bandage onto an intestinal wound [217]. Reproduced with permission Copyright 2024 Nature Electronics. (e) Schematic illustration of our device, which includes a sparse collection of metal disks embedded in a thin hydrogel and Miniaturized designs allow for implantation by laparoscopic surgery. and (f) The BioSUM enables ultrasonic monitoring of homeostasis in deep tissues. and (g) Schematic illustration of a BioSUM for detecting postsurgical leakage from the stomach, small intestine, and pancreas. and (h) pH-responsive ranges for BioSUM1, BioSUM2, and BioSUM3, and the corresponding pH values of representative digestive juices [218]. Reproduced with permission Copyright 2024 Science. (i) Schematic of oral capsule - type microneedles: In-Vivo ingestion, transit, magnetic-triggered deployment, and drug release mechanism [219]. Reproduced with permission Copyright 2024 Device.

MN technology has also been applied to modulate mitochondrial oxidative stress, a key pathological feature of PD. Liu et al. [215] introduced MNs loaded with mitochondrially-targeted liposomes (MFeI MNs) encapsulating single-atom iron nanozymes (Fig. 18b). By targeting neuronal mitochondria and scavenging ROS, these MNs showed significant efficacy in MPTP-induced PD models. Compared to systemic intravenous injection, in situ MN administration facilitated higher drug accumulation in critical lesion areas, such as the substantia nigra pars compacta and striatum, effectively alleviating behavioral deficits and neuroinflammation.

Alongside targeted enzyme therapies, the delivery of endogenous signaling molecules has emerged as a neuroprotective strategy. Balakrishnan et al. [220] engineered PVA/trehalose-based MN arrays for the sustained delivery of AP39, a hydrogen sulfide (H₂S) donor. This platform achieves high skin accumulation and continuous release of H₂S, which mitigates oxidative stress, reduces tau protein levels, and inhibits neurodegeneration in cellular models. The applications of microneedles in neurological disease therapy are summarized in Table 14.

Table 14.

Applications of microneedles in Neurological Diseases.

Specific MN System	Drugs	Mechanisms	References
SLN - RV - TG	Rivastigmine (SLN-NPs)	Trigeminal nerve delivery via facial skin; bypasses the BBB; thermosensitive gel formation ensures sustained release.	[214]
CD - MOFs/MN	Huperzine A (Hup A)	Nose-to-brain delivery via HA-based MNs; CD-MOFs enhance drug solubility and prevent nasal mucosal clearance.	[30]
MFeI MNs	Mito@Fe - ISAzyme	Mitochondrial-targeted nanozymes; direct delivery to the substantia nigra and striatum for potent ROS scavenging.	[215]
PVA/MN + AP39	AP39 (H2S donor)	Provides mitochondrial neuroprotection; trehalose-stabilized matrix ensures high mechanical strength and controlled release.	[220]

While the use of peripheral anatomical pathways, such as the trigeminal nerve and olfactory routes, to bypass the BBB represents a significant conceptual advancement, several translational challenges remain. The trigeminal route requires precise facial MN application over the V1-V3 dermatomes, which may be difficult for patients to perform correctly during self-administration. Furthermore, the toothbrush-shaped nasal system introduces potential risks of choking and nasal mucosal trauma that are not present in conventional intranasal sprays. Although mitochondrial-targeted nanozymes show effective ROS scavenging, current studies lack evidence that MN-delivered cargoes alter the disease trajectory beyond symptomatic relief. The absence of neuroprotective biomarker data, such as cerebrospinal fluid neurofilament light chain levels or striatal dopamine transporter imaging, limits claims of disease modification. Additionally, the chronic administration required for neurodegenerative diseases (spanning years to decades) is incompatible with single-use disposable patches; the cumulative cost, medical waste, and patient burden would likely exceed those of a single implanted intracerebroventricular catheter with a refillable reservoir.

In summary, recent studies demonstrate that the BBB can be bypassed via peripheral routes rather than merely penetrated. However, rather than focusing on chronic disease management where MN platforms face fundamental limitations, neurological applications may be better suited for acute neuroprotective interventions, such as peri-stroke antioxidant delivery or post-traumatic brain injury anti-inflammatory treatment. In these scenarios, the minimally invasive advantages of MNs are maximized, and the treatment duration is finite. Future research could explore dynamic feedback-regulated systems that sense localized neurochemical changes (e.g., glutamate, dopamine, cytokines) for on-demand release. However, before clinical translation, the biomechanical compliance and long-term neurological safety of such systems must be validated in large-animal primate models.

2.9. Applications of MNs in other diseases

MN technology has evolved from its initial applications in dermatology and wound management to a versatile platform for systemic and localized drug delivery. Recent studies have demonstrated the utility of MNs in treating diverse conditions, including alopecia, hepatic disorders, gynecological diseases, and neurological or psychiatric conditions. By overcoming physiological barriers and enabling targeted, controlled release of therapeutics, MN systems address critical limitations of conventional administration routes. Consequently, the continued integration of advanced biomaterials with MN designs holds significant potential for expanding clinical indications and improving patient outcomes across multiple medical disciplines.

2.9.1. Applications of MNs in intestinal diseases

Oral delivery of biopharmaceuticals is limited by the proteolytic environment of the gastrointestinal (GI) tract and the transient nature of mucosal contact. To overcome rapid clearance and poor bioavailability, research has focused on autonomous and site-specific delivery platforms that utilize gut biomechanics. Inspired by pufferfish morphology, Gao et al. [216] engineered an intestinal peristalsis-driven microneedle robot (Fig. 18c). This biomimetic system uses endogenous luminal contractions as a mechanical actuator to trigger the radial expansion of barbed MNs, ensuring stable penetration into the mucosal wall. To address intestinal wound healing, Wu et al. [217] developed a biodegradable electronic bandage composed of a PCL matrix and Mg-Mo microelectrodes (Fig. 18d). This tissue-adhesive interface provides localized dual electrical stimulation, facilitating re-epithelialization and reducing the risk of hyperplastic strictures associated with conventional sutures.

Beyond active repair, real-time diagnostic monitoring of deep-tissue homeostasis is a key area in gastroenterology. Liu et al. [218] developed a bioresorbable, shape-adaptive ultrasonic sensor (BioSUM) for the non-invasive detection of post-surgical GI leakages (Fig. 18e–h). By embedding resorbable metal disks within a pH-responsive hydrogel, the BioSUM translates localized chemical changes into measurable structural swelling, which can be detected via standard ultrasound. This diagnostic approach offers an alternative to secondary surgical removal, providing continuous monitoring during the high-risk postoperative period.

The precision of these systems has been improved through external guidance mechanisms to address the unpredictable transit of capsules. Levy et al. [219] introduced a magnetically triggered ingestible capsule for the deployment of drug-loaded MNs (Fig. 18i). Using external handheld magnets, clinicians can activate the MN array on demand at specific anatomical sites, maximizing localized drug concentrations while maintaining a favorable biosafety profile.

The integration of soft robotics, bioelectronics, and MN technology for gastrointestinal applications represents a significant advancement; however, several translational challenges remain. The peristalsis-driven MN robot relies on the assumption that intestinal peristalsis is sufficiently forceful and directional for barbed penetration. In practice, postprandial peristalsis is highly variable, and barbed anchoring may cause mucosal laceration during retrograde contractions, a safety concern not addressed in the reviewed studies. The BioSUM sensor addresses anastomotic leak detection, but standard clinical methods already achieve satisfactory detection rates; the added clinical and economic value of a resorbable ultrasonic sensor requires further validation. Additionally, the magnetically triggered ingestible capsule requires real-time fluoroscopic guidance and clinician operation for activation, which limits patient autonomy and increases procedural complexity.

Table 15 summarizes these advancements. However, gastrointestinal MN platforms face anatomical challenges: the primary function of the GI tract is propulsion and absorption, and prolonged mucosal adhesion by MNs may trigger foreign body responses or obstructive complications. Rather than focusing on chronic drug delivery, which is poorly suited to the GI environment, development should prioritize localized, short-duration interventions, such as post-polypectomy hemostasis and targeted colorectal cancer chemotherapy. Future success in these applications requires ensuring material stability across fluctuating enzymatic environments, ultimately establishing viable standards for indication-specific gastroenterology.

Table 15.

Applications of microneedles in Intestinal Diseases.

Specific MN System	Drug	Mechanism	Limitations	References
Peristalsis - driven Robot	Insulin	Pufferfish-inspired design; uses intestinal peristalsis to drive barbed MNs for mucosal penetration and retention.	Lacks human trials; impact of gastric emptying and motility variations needs study.	[216]
E-bandage	\	PCL/Mg-Mo microelectrodes with adhesive hydrogel; provides dual electrical stimulation to accelerate tissue regeneration.	Tested only in rodents; requires clinical validation and optimization of stimulation parameters.	[217]
BioSUM	\	pH-responsive hydrogel with bioresorbable metal disks; enables real-time ultrasound imaging of localized pH levels.	Clinical feasibility and long-term human safety profiles are pending.	[218]
Magnetic capsule	Drug-loaded microneedles	External magnetic triggering releases MNs at specific intestinal sites; achieves localized high-concentration delivery.	Murine-based study; requires extensive human clinical validation.	[219]

2.9.2. Applications of MNs in wrinkles

Dermatological conditions, ranging from chronic wounds to UV-induced photoaging, require deep-tissue penetration with minimal systemic exposure. The SC limits the efficacy of conventional topical formulations, often necessitating high doses that cause local irritation. MN arrays address this challenge by bypassing the SC to deliver therapeutic agents directly into the viable epidermis and dermis. This approach enables the intradermal deployment of diverse cargoes, from bioactive hydrogels for wound remodeling to genetic payloads for cellular modulation.

Recent advancements in skin management focus on active microenvironment remodeling. To address fibroproliferative scarring, Zhang et al. [221] developed a biomimetic hydrogel (P&G@LMs) that combines active contraction with antioxidant activity (Fig. 19a). By regulating the inflammatory-fibrotic axis, this platform promotes organized collagen deposition, effectively reducing scar area in full-thickness wound models.

Fig. 19.

(a) Schematic of biomimetic mechanical hydrogel (P&G@LMs) promoting skin wound repair [221]. Reproduced with permission Copyright 2025 Bioactive Materials. (b) Schematic diagram of the mechanism by which HA/PX@MNs microneedles improve skin photoaging [222]. Reproduced with permission Copyright 2024 International Journal of Biological Macromolecules. (c) Fabrication process and working principle of the GCMNs [223]. Reproduced with permission Copyright 2025 Advanced Materials. (d) Graphical abstract shows the preparation process of the MN patch and its application for facial anti-aging [224]. Reproduced with permission Copyright 2023 Advanced Healthcare Materials.

In the context of photoaging, MN innovations increasingly integrate materials science with bioelectronics. Tang et al. [222] enhanced the transdermal delivery of HA using a composite array (HA/PX@MNs) to scavenge free radicals and upregulate ECM gene expression, thereby mitigating UV-induced wrinkles (Fig. 19b). To further enhance this effect, Lin et al. [223] introduced a self-powered galvanic cell MN patch (GCMN) (Fig. 19c). This system generates localized microcurrents and releases magnesium and hydrogen ions to accelerate collagen regeneration, providing a combined bio-physical approach to counteract oxidative stress.

Intradermal delivery of genetic materials represents a significant development in aesthetic dermatology. Lv et al. [224] demonstrated the use of flexible-base dissolving MNs for the co-delivery of hydrolyzed collagen and nicotinamide to restore dermal density (Fig. 19d). Expanding on this, You et al. [225] utilized cellular nanoporation to encapsulate COL1A1 mRNA within EVs. When integrated into an MN array (COL1A1-EV MN), this platform facilitates the in situ synthesis of type I collagen, targeting the underlying protein depletion in aged skin. The clinical potential of this approach was evaluated by Xing et al. in a human trial (n = 30), where polypeptide-loaded MNs (CP-DMNs) significantly improved periorbital and nasolabial wrinkles with a favorable safety profile [226]. The applications of MNs in wrinkle treatment are summarized in Table 16.

Table 16.

Applications of microneedles in Wrinkle.

MN Formulation/Designation	Therapeutic Components	Mechanism	Limitations	References
P&G@LMs	Antioxidant, anti-inflammatory components	Biomimetic contraction; modulates inflammation/fibrosis to promote organized collagen deposition.	Validated in mouse models; requires human clinical verification.	[221]
HA/PX@MNs	Hyaluronic acid + PX (antioxidant)	Synergistic hydration and ROS scavenging; upregulates ECM gene expression and fibroblast activity.	Further clinical studies are necessary for translational potential.	[222]
GCMN	Mg electrodes (generate microcurrent, H2, Mg2+)	Generates therapeutic microcurrent, H2, and Mg2+; promotes collagen regeneration and cell viability.	Biocompatibility and long-term effects in humans require deeper exploration.	[223]
HC/DMN	Hydrolyzed collagen + Nicotinamide	Optimized mechanical strength for deep penetration; rapid dissolution to deliver rejuvenating payloads	Long-term safety profiles and large-scale clinical trials are pending.	[224]
COL1A1-EV MN	EVs loaded with COL1A1 mRNA	Replenishes aged-related collagen loss via mRNA-encoded EV delivery; boosts fibroblast productivity.	Early-stage approach; clinical feasibility and durability remain unknown.	[225]
CP-DMNs	Composite anti-wrinkle polypeptides	HA + PVP matrix; enhances peptide transdermal delivery	Limited human sample size; necessitates broader clinical validation.	[226]

Although aesthetic dermatology is a commercially mature application for MN technology, it faces significant translational and regulatory challenges. Current anti-aging studies predominantly rely on surrogate endpoints, such as histological collagen density or 3D imaging of wrinkle depth, rather than validated long-term clinical outcomes. The cited human trial (Xing et al.) lacked randomization, blinding, and long-term follow-up, which limits its clinical validity. Furthermore, while COL1A1 mRNA-EV delivery presents a novel mechanism, the regulatory pathway for cosmetic mRNA products remains unclear. Unlike therapeutic mRNA vaccines, cosmetic applications may require extensive safety testing, including carcinogenicity and genotoxicity evaluations, which could impact economic feasibility. Additionally, preclinical studies frequently use young murine models (2-3 months) to evaluate anti-aging effects, which does not accurately replicate the pathophysiology of photoaging in middle-aged or elderly human skin.

The development of dermatological MNs is moving toward molecularly targeted interventions. However, rather than focusing solely on complex diagnostic-therapeutic systems, aesthetic MN platforms must meet the same evidentiary standards as therapeutic devices, including randomized controlled trials with adequate follow-up. The current lack of rigorous clinical validation in cosmetic MN research may undermine the credibility of the field and invite stricter regulatory scrutiny. Future research should prioritize robust clinical evidence over surrogate endpoints and focus on immunomodulatory interfaces capable of modulating chronic inflammatory microenvironments, ensuring that these high-precision platforms are reliably translated into clinical practice.

2.9.3. Applications of MNs in hair loss

Alopecia is a prevalent condition with significant psychosocial impacts, affecting over half of the population with an increasing incidence rate [227,228]. Although pharmacological treatments such as minoxidil and finasteride are clinically established, their efficacy is often limited by systemic side effects and the metabolic barrier of the scalp, while surgical transplantation is cost-prohibitive for many patients [229]. In this context, MN arrays offer a targeted delivery approach by bypassing the SC to deliver therapeutic payloads, ranging from small molecules to biological macromolecules, directly into the dermal papilla (DP) microenvironment [230,231]. Recent studies indicate that MN-mediated delivery of exosomes, nanoformulations, and growth factors can effectively reactivate dormant hair follicles [232,233].

Recent research has shifted from passive drug delivery to the use of regenerative biologics. For example, Shi et al. [234] developed a drug-free MN array incorporating chitosan lactate (CL) and adipose stem cell-derived exosomes (EXO) (Fig. 20a). This platform promotes the transition from the telogen (resting) phase to the anagen (growth) phase by stimulating dermal papilla cell (DPC) proliferation, while the inherent antimicrobial properties of the matrix help maintain scalp homeostasis. Additionally, inorganic-organic hybrid systems have been explored for androgenetic alopecia (AGA). Zhang et al. [235] designed a mesoporous silica nanocomposite MN array (ZCQ/MN) doped with quercetin and zinc/copper (Fig. 20b). This system protects follicles from dihydrotestosterone (DHT)-induced damage and modulates localized inflammation to support follicle maturation.

Fig. 20.

(a) Schematic of composition, skin insertion, needle separation, and therapeutic mechanism of (EXO + CL)/MN as applied for hair regeneration [234].Reproduced with permission Copyright 2022 Advanced Healthcare Materials. (b) Schematic illustration of ZCQ/MN for AGA [235]. Reproduced with permission Copyright 2023 Bioactive Materials. (c) Schematic illustration of the treatment of androgenetic alopecia (AGA) with MXD MN patches [51].Reproduced with permission Copyright 2023 ACS Applied Materials & Interfaces. (d) The main mechanism of action of Gel-PFD MNP in the treatment of chronic liver fibrosis [236]. Reproduced with permission Copyright 2023 Materials Today Advances. (e) Mechanism of Gel-nintedanib MNP for the treatment of chronic liver injury and (f) The Gel-nintedanib MNP (microneedle patch) is fabricated by using a vacuum casting method after crosslinking the mixed hydrogel through photopolymerization and (g) The figure below illustrates the primary functions and characteristics of the microneedle patch [237]. Reproduced with permission Copyright 2025 Advanced Composites and Hybrid Materials. (h) Schematic illustration of in situ endometrial repair by antioxidant nanozyme microneedles with stem cell loading [238]. Reproduced with permission Copyright 2022 Chemical Engineering Journal.(i) Schematic illustration of the in situ intrauterine repair by MN/En-ADV [239]. Reproduced with permission Copyright 2022 Small.

To improve patient compliance in chronic hair loss management, recent studies have focused on creating intradermal drug reservoirs. Yin et al. [51] developed a dissolvable MN array integrated with minoxidil (MXD)-loaded PLGA microspheres (Fig. 20c). By enabling the sustained release of MXD within the dermis, this system reduces the administration frequency while maintaining a pro-growth effect in AGA models. The applications of MNs in hair loss treatment are summarized in Table 17.

Table 17.

Applications of microneedles in Hair Loss.

MN Formulation/Designation	Drugs/Active Ingredients	Mechanism of Action	Limitations	References
(CL + EXO)/MN	Chitosan Lactate (CL) + Adipose-Derived Stem Cell Exosomes (EXO)	Accelerates the telogen-to-anagen transition; promotes proliferation and migration of dermal papilla cells (DPCs).	Murine-based study; requires extensive human clinical validation.	[234]
ZCQ/MN	Quercetin (Qu) - Doped Zinc/Copper Mesoporous Silica Nanocomposite	Protects follicles from DHT-induced damage; modulates inflammatory niche to promote follicle maturation.	Clinical feasibility and long-term human safety profiles are pending.	[235]
MXD MN	Polylactic - Glycolic Acid (PLGA) + minoxidil (MXD)	Enables sustained drug release via polymer microspheres; significantly reduces dosing frequency and systemic side effects.	Requires large-scale comparative trials against conventional topical MXD.	[51]

While MN technology offers a pharmacokinetic advantage for AGA by bypassing the scalp barrier to enhance minoxidil bioavailability, several translational challenges remain. Testosterone-treated C57BL/6 mice exhibit different follicle cycling kinetics compared to human AGA; the rapid, synchronized murine cycling differs from the progressive miniaturization seen in humans over years, making short-term (4-8 weeks) efficacy data difficult to translate clinically. Although exosome-mediated follicle reactivation shows potential, the regulatory classification of cell-derived extracellular vesicles remains ambiguous across jurisdictions (e.g., FDA, EMA, NMPA). The lack of standardized manufacturing, potency assays, and immunogenicity thresholds poses challenges for commercial development. Furthermore, MN-mediated minoxidil delivery lacks head-to-head comparisons with 5% topical foam. Given the low cost, established safety, and adequate efficacy of the foam, the clinical and economic advantages of a more complex MN system require further validation.

Future research in trichological MNs should focus on specific clinical indications rather than competing with first-line options for routine AGA. Two potential target populations are minoxidil non-responders (30-40% of AGA patients), where enhanced follicular penetration may improve treatment outcomes, and alopecia areata, an autoimmune condition lacking FDA-approved topical therapies, where MN-mediated delivery of corticosteroids or JAK inhibitors could address current treatment gaps. In these specific indications, MN platforms that simultaneously modulate oxidative stress, antagonize androgen receptors, and promote angiogenesis may provide a favorable microenvironment for follicle reactivation, provided that the stability of multi-target payloads is validated against established topical treatments.

2.9.4. Applications of MNs in liver diseases

Liver diseases, particularly liver fibrosis and chronic injury, represent a significant global health burden, yet conventional therapeutic interventions remain limited by suboptimal drug distribution and systemic side effects. To address these clinical challenges, MN technology has emerged as a promising strategy for targeted hepatic intervention. Initially focusing on enhancing the pharmacokinetics of established anti-fibrotic agents, Gu et al. [236] developed a GelMA-based hydrogel microneedle patch for the sustained intradermal delivery of pirfenidone (PFD) (Fig. 20d). This platform facilitates the long-term release of PFD and effectively inhibits fibroblast migration while modulating macrophage polarization. In chronic liver fibrosis models, the Gel-PFD MN demonstrated significant efficacy in normalizing liver enzyme levels and attenuating apoptosis, offering a minimally invasive strategy to reduce the treatment burden on patients.

As the understanding of liver pathophysiology has advanced, research has shifted toward integrated approaches combining regenerative medicine with catalytic therapy. Addressing the limitations of traditional stem cell therapy, such as immune rejection and low delivery efficiency of the secretome [240], Xu et al. [241] introduced an MN array integrating soy protein isolate (SPI), stem cell secretome-encapsulated nanoparticles (SecNPs), and platinum-based nanozymes (PtNZs). This system utilizes the SOD- and CAT-like activities of PtNZs to scavenge ROS and alleviate hypoxia, while the SecNPs provide anti-inflammatory and hepatoprotective effects. Facilitated by NIR responsive drug release, this multifunctional array significantly mitigates liver fibrosis and restores hepatic function in murine models, as supported by transcriptome analysis.

Recent advancements in hepatological MN technology focus on the sequential and hierarchical delivery of synergistic therapeutic cargoes. Recognizing that chronic liver injury involves both progressive fibrosis and impaired hepatocyte regeneration, Song et al. [237] engineered a multilayered drug-release MN array (H@EV-H/G/N MN) utilizing mHA and mGL matrices (Fig. 20e–g). This structure features an inner layer for the sustained release of the anti-fibrotic agent nintedanib and an outer layer encapsulating HGF-enriched stem cell exosomes (HGF@EV). By simultaneously inhibiting M2 macrophage polarization and promoting hepatocyte proliferation, this dual-delivery system effectively reverses tissue fibrosis and restores metabolic homeostasis. In addition to therapeutic remodeling, recent studies have explored real-time metabolic surveillance. Zhu et al. [242] engineered a nanostructured bioelectrode microneedle (RNB-MN) platform capable of assessing organ function. By optimizing a bilayer fabrication protocol that pairs a gold adhesion interlayer with a stress-mitigated dealloying technique, these mechanically robust RNB arrays resist shear fracture within stiff tissue matrices. Integrating an aptamer-based biosensing framework, this platform achieved continuous pharmacokinetic tracking of low-therapeutic-index drugs in vivo, identifying functional drug-clearance fluctuations triggered by acute liver injury earlier than conventional clinical serum biomarkers [242]. Table 18 summarizes the applications of microneedles in liver diseases.

Table 18.

Applications of microneedles in Liver Diseases.

MN Formulation/Designation	Therapeutic Agents	Function	Action mechanisms	Limitations	References
Gel - PFD MNP	Pirfenidone (PFD)	Anti-fibrotic & hepatoprotective	GelMA-mediated sustained release of PFD to inhibit fibrotic markers and restore liver enzymes.	Limited to murine models; lacks large-animal data and safety testing for varied etiologies.	[236]
Smart SPI/PVA microneedle	Stem cell secretome, platinum nanozymes, neutral protease	Multifunctional liver recovery	NIR-triggered core-shell release; Pt nanozymes scavenge ROS via photothermal effects to protect hepatocytes.	The SecNP mechanism requires clarification; loading capacity and clinical safety need further optimization.	[241]
H@EV - H/G/N MNP	Nintedanib + HGF - exosomes	Regenerative fibrosis inhibition	Biphasic layered release: Nintedanib suppresses fibrosis while HGF-exosomes drive hepatocyte restoration.	Murine-based study; long-term effectiveness across different types of liver injury remains unknown.	[237]
Nanostructured RNB-MN	Aptamer-functionalized nanostructured bioelectrode	Real-time liver function surveillance	Dealloyed nano-cavities optimize electrochemical potential window for continuous tracking of pharmacokinetic drug clearance and early liver injury detection	Long-term biosafety of indwelling bioelectrodes in hyper-dynamic human chronic tissues requires multi-year evaluation	[242]

The extension of MN technology to hepatic fibrosis presents a significant anatomical challenge that questions the fundamental definition of “transdermal” delivery; it is necessary to evaluate whether this approach is justified by clinical necessity or technological opportunism. Bypassing hepatic first-pass metabolism may paradoxically increase the systemic toxicity risk for hepatotoxic drugs (e.g., nintedanib); none of the reviewed studies addressed whether elevated systemic exposure via dermal reservoirs improves hepatic targeting or merely redistributes toxicity to renal and gastrointestinal organs. The RNB-MN biosensing platform measures drug clearance in dermal interstitial fluid as a surrogate for hepatic function, a validity that remains questionable given complex hepatic extraction ratios and protein binding kinetics. Furthermore, the SPI/PtNZ system employs NIR-responsive release, yet the liver is inaccessible to external irradiation without abdominal wall penetration, raising anatomical feasibility concerns similar to those in cardiac applications.

The development of microneedle-mediated hepatotherapy represents a shift toward hierarchical modulation. However, rather than claiming “liver-targeted delivery” (which is unachievable without surgical access), MN-mediated hepatotherapy should be considered as “systemic delivery with reduced hepatic first-pass loss"-a pharmacokinetic refinement with niche applications for drugs with high extraction ratios and narrow therapeutic windows. Within this specific context, metabolism-triggered architectures responsive to hepatic biomarkers (ALT/AST) and rigorous pharmacokinetic validation in non-rodent models may advance the field, provided that anatomical feasibility and toxicity redistribution are thoroughly addressed prior to clinical translation.

2.9.5. Applications of MNs in uterine disease

MN technology is increasingly applied in reproductive health, transitioning from systemic hormonal regulation to structural uterine repair. To address the need for user-friendly, on-demand hormonal contraception, Altuntaş et al. [243] engineered a bilayer dissolving MN array (NES-NS-DMNs) encapsulating a Nestorone (NES) nanosuspension. Using a PVA/PVP matrix and an optimized nanoprecipitation-ultrasonication protocol, this system achieves a high drug loading of 2.26 mg per array with high mechanical resilience. In vivo pharmacokinetic profiles in rats showed a rapid peak plasma concentration within 1 h, maintaining therapeutic levels (above 3.4 ng/mL) for two days. This minimally invasive, self-administered platform provides a practical alternative to conventional oral or injectable contraceptives, ensuring high bioavailability and patient compliance.

Beyond pharmacological delivery, MN platforms are being explored for complex tissue engineering, particularly for treating infertility induced by endometrial injury. Zhu et al. [238] developed a multifunctional MN system for deep-seated uterine repair (Fig. 20h). This GelMA-based scaffold integrates umbilical cord perivascular stem cells (UCA-PSCs) at the needle tips with embedded cerium dioxide (CeO₂) nanozymes in the backing layer. This dual-functional architecture alleviates oxidative stress via the catalytic scavenging of ROS while promoting paracrine-mediated tissue regeneration. In long-term animal models, this system restored endometrial thickness to near-normal levels (561.2 μm) within 90 days, enhancing neovascularization and smooth muscle regeneration. The treated uteri supported embryo implantation and development to late-stage pregnancy, indicating a recovery of both morphological integrity and reproductive function.

For refractory conditions such as Asherman's syndrome (AS), Li et al. [239] introduced an antibacterial MN patch (MN/En-ADV) loaded with human endometrium-derived adventitial cell (En-ADV) spheroids (Fig. 20i). Using a GelMA matrix functionalized with lactoferrin (LF), this system provides an antibacterial and biocompatible microenvironment. A surface micro-hole structure induces the formation of three-dimensional (3D) cell spheroids, which exhibit upregulated regenerative genes (e.g., Ki67, PCNA) and enhanced pro-angiogenic capabilities compared to traditional dispersed cell therapies. Animal experiments showed that the MN/En-ADV system restored glandular density and alleviated fibrosis, achieving a 100% pregnancy rate in injury models. The applications of microneedles in uterine disease treatments are summarized in Table 19.

Table 19.

Applications of microneedles in Uterine Disease Treatments.

MN Formulation/Designation	Key Components	Function	Action mechanisms	References
NES-NS-DMNs	Nestorone (NES)	On-demand contraception	Contraception Nanoparticle-mediated rapid systemic absorption for minimally invasive self-contraception	[243]
UCA-PSCs/CeO2-MN	UCA-PSCs, CeO2 Nanozymes	Uterine niche restoration	Nanozyme ROS scavenging and stem cell therapy to restore uterine wall thickness and vascularization.	[238]
MN/En-ADV	En-ADV Spheroids, Lactoferrin (LF)	Endometrial regeneration	Induces 3D cellular spheroids for accelerated endometrial remodeling and high embryo implantation.	[239]

While the application of MN technology to reproductive health addresses important clinical needs, anatomical and regulatory complexities introduce constraints that require further evaluation. The uterine cavity presents a unique biomechanical environment, including cyclical endometrial shedding, dynamic cervical mucus barriers, and ascending infection risks from vaginal flora. The MN/En-ADV system for AS lacks data on menstrual cycle compatibility; it remains unclear whether the GelMA scaffold withstands menstrual flow without dislodgement or whether lactoferrin maintains efficacy in protease-rich menstrual blood. Although UCA-PSCs/CeO₂-MN restored endometrial thickness to 561.2 μm, this metric in healthy young mice may not directly translate to human clinical endpoints, where endometrial receptivity (assessed via histological dating, pinopode expression, and molecular markers) is the primary determinant of implantation success. Furthermore, the Nestorone contraceptive patch competes against long-acting reversible contraceptives (LARCs, such as IUDs and implants) with >99% efficacy and 3-10-year durations; the clinical advantage of a bi-weekly self-administered patch, which requires strict compliance and carries a higher failure risk, may be limited to specific populations.

Although these studies demonstrate progress in material design, functional integration, and cell microenvironment regulation, reproductive MN platforms must undergo rigorous menstrual cycle-phase stratification in preclinical models and demonstrate non-inferiority to existing LARCs before clinical translation. Rather than claiming definitive cures for refractory infertility, future development should focus on hysteroscopic-compatible deployment techniques and the stabilization of cell-laden 3D spheroid functionality within indication-specific applications where conventional pharmacotherapy is insufficient.

2.9.6. Applications of MNs in schizophrenia

MN technology offers a potential alternative for the long-term management of schizophrenia by addressing the clinical limitations of conventional oral formulations. By enabling sustained drug release over weeks to months via biodegradable polymer matrices, MN-based transdermal systems bypass the hepatic first-pass effect and reduce the interindividual variability associated with gastrointestinal metabolism. This stabilization of plasma drug levels can mitigate dose-related adverse reactions, such as extrapyramidal symptoms. Additionally, the minimally invasive administration may improve treatment continuity, particularly in patients with cognitive impairment and poor illness insight.

To advance this approach, Li et al. [244] developed a PLGA-based implantable MN patch (IMN) for the delivery of risperidone. Using a two-step casting method to load the drug into the needle tips, supported by a PVA-PVP composite backing layer, the IMN achieved an insertion depth of up to 504 μm. In vivo rodent models showed that plasma concentrations remained within the therapeutic window for nine days, with a relative bioavailability of 49.5%. To address the delayed onset typical of long-acting formulations, Zhao et al. [245] combined a dissolvable MN array patch (DMAP) with an implantable MN array patch (IMAP). The DMAP component, utilizing nanocrystals, provided rapid drug release (20.01% transdermal efficiency within 24 h), while the IMAP ensured a 14-day sustained release via gradual PLGA degradation.

Research has also extended the application of psychiatric MNs to highly lipophilic prodrugs, which are challenging for aqueous-based transdermal systems. Evaluating the pharmacological properties of fluphenazine and its decanoate prodrug, Abu Ershaid et al. [246] compared dissolvable MNs, nanoemulsion-loaded MNs, and PLGA tip-loaded MNs. The PLGA tip-loaded formulation demonstrated the highest efficacy, achieving a cumulative release rate of 89.91% over 21 days. In vivo studies confirmed that plasma concentrations remained within the therapeutic window (1-10 ng/mL) for over one week, yielding a relative bioavailability of 42.45%. The applications of microneedles in schizophrenia are summarized in Table 20.

Table 20.

Applications of microneedles in Schizophrenia.

MN Formulation/Designation	Drugs	Function	Advantage	References
RIS IMN	Risperidone (RIS)	Transdermal delivers risperidone to achieve long-acting self-administered treatment.	excellent drug-loading performance, good mechanical properties, enables long-acting drug release and self-administration	[244]
DMAP and IMAP	Paliperidone (PPD)	Delivers paliperidone and avoids the initial therapeutic lag of traditional long-acting formulations.	The combined use of DMAP and IMAP avoids the initial therapeutic lag of traditional long-acting formulations.	[245]
FLU-D-MNs, FLU-D NE -MNs, and FLU-PLGA -MNs	Fluphenazine (FLU) and its prodrug fluphenazine decanoate (FLU-D)	All achieve systemic delivery of fluphenazine.	The three MN systems developed offer patients a user-friendly, painless, and convenient long-acting delivery method for FLU	[246]

Although MN-based long-acting antipsychotic delivery aims to address treatment non-adherence, which affects 40-60% of schizophrenia patients, several design and clinical limitations remain. The reported pharmacokinetic profiles (9-day release for risperidone IMN, 14-day for the DMAP/IMAP system) are substantially shorter than those of current long-acting injectables (LAIs), which range from 2 to 4 weeks for paliperidone palmitate to 3 months for aripiprazole monohydrate. This necessitates more frequent administration, potentially reducing the benefit for patients with poor treatment engagement. Furthermore, a relative bioavailability of 42-49% indicates significant drug loss due to skin retention, enzymatic degradation, or incomplete absorption, raising concerns regarding cost and efficiency. Importantly, non-adherence in schizophrenia is primarily driven by psychosocial factors, such as lack of insight, cognitive impairment, and stigma, rather than merely the route of administration. Therefore, relying solely on delivery technology without addressing these underlying psychosocial barriers is insufficient.

The integration of MN technology into schizophrenia management may offer specific clinical benefits, but it should not directly compete with established LAIs for chronic maintenance. Instead, MN-mediated antipsychotic delivery is better suited for specific clinical scenarios, such as early psychosis intervention, where patients retain insight and may prefer less stigmatizing options, or transitional care, bridging hospital discharge to outpatient LAI initiation. Within these specific applications, future research should focus on optimizing long-term tissue biocompatibility and validating mechanical robustness. Ultimately, the clinical success of MN platforms depends on their integration into comprehensive, multidisciplinary care coordination rather than functioning as isolated adherence solutions.

Based on a systematic analysis of bioactive microneedles (Bioactive MNs) across various disease models, it is evident that MN technology has advanced beyond simple physical penetration and passive diffusion. To address the specific anatomical barriers, biomechanical constraints, and pathological microenvironments of solid organs, mucosal tissues, and complex wounds, MN design has shifted toward disease-specific engineering and responsive microenvironmental modulation. Consequently, bioactive MN systems have evolved into customized platforms that integrate advanced structural designs and functional materials to tackle specific clinical challenges. To systematically summarize how these systems address key therapeutic bottlenecks and to highlight their inherent biophysical and biological limitations across different applications, Table 21 provides a comprehensive comparison of the representative MN platforms discussed in this review. This framework details their core engineering features, therapeutic payloads, stimuli-responsive release mechanisms, biosafety profiles, and manufacturing strategies, offering a practical overview of their translational potential from both biomedical engineering and industrial perspectives. Overall, these systems demonstrate the evolution of MN technology from a conventional transdermal delivery tool into an integrated, responsive, and disease-adaptive therapeutic interface.

Table 21.

Summary of diseases and representative microneedle systems.

No.	Disease/Application	Representative MN System	Disease Model	Therapeutic Payload	Microneedle Geometry	Release Behavior	Biosafety Evaluation	Manufacturing Strategy
1	Psoriasis	Living-cell perforating MN	IMQ-induced murine psoriasis model	Living egulatory T cells (Tregs)	3D-printed rigid array with perfusable microchannels	Active dermal infiltration via chemotaxis; non-dissolving implant-mediated delivery	Long-term monitoring of foreign-body response from rigid inorganic scaffold	High-precision polymer micro-3D printing + sterile cell encapsulation
2	Hypertrophic scar	Microenvironment-responsive detachable MN	Rabbit ear hypertrophic scar model	ROS/MMP dual-responsive 5-FuA prodrug	Detachable heterogeneous structure with crosslinked microneedle tips	Site-retained tips trigger bond cleavage under pathological ROS/MMP for on-demand release	Evaluation of degradation byproducts and local toxicity window	Gradient mold casting + UV curing
3	Acne vulgaris	Photo-/chemical dual-responsive hierarchical MN	C. acnes-induced murine model	Curcumin + Cur-loaded mesoporous polydopamine (Cur-MPDA) NPs	Core–backplate hierarchical HA/fucoidan hybrid scaffold	pH-triggered dissolution (pH ∼5.0) + 808 nm NIR-induced burst release	Nanomaterial biocompatibility; thermal safety threshold control (42–45°C)	Gradient vacuum casting + layer-by-layer curing
4	Diabetic wound	Self-powered electroactive MN	MRSA-infected murine foot ulcer model	DFO + microelectrically driven angiogenic factors	Conductive hydrogel MN integrated with piezoelectric film	Mechanical-to-electrical conversion enabling ion migration (Nernst–Planck-driven)	Long-term cytotoxicity of anodic dissolution products	Flexible microelectronic printing + precision assembly
5	Oral ulcer	Catechol-based ionic liquid adhesive MN	Aphthous ulcer model	Diclofenac sodium + poly-ionic liquid matrix	Short blunt conical array optimized for shear resistance	Saliva-triggered swelling with wet adhesion (≈16.2 kPa) and sustained release	Oral mucosal compatibility and erosion safety	PDMS mold casting under ultrasonic vacuum
6	Cancer therapy	Ultrasound-responsive silk pyroptosis MN	Melanoma tumor model	2D Cu-TCPP MOF nanosheets + anti-PD-1 antibody	High aspect ratio rigid pyramidal array	Ultrasound-triggered ROS burst via sonodynamic therapy inducing pyroptosis	Renal clearance and long-term nanomaterial metabolism	Vacuum casting + low-temperature drying to preserve antibody activity
7	Ophthalmic disease	Annular self-dissolving MN	Infectious keratitis/stromal disease	Levofloxacin/Cyclosporine A	Annular array with central optical aperture	Rapid tear-fluid infiltration-triggered dissolution and stromal diffusion	Optical transparency, corneal neovascularization monitoring	Femtosecond laser microfabrication/annular mold casting
8	Musculoskeletal/IVDD	Optogenetic exosome TENG screw MN	Intervertebral disc degeneration model	Optogenetically engineered extracellular vesicles	High-strength elongated screw-like MN array	Mechanical motion-driven piezoelectric activation triggering EV release	Fatigue resistance and EV viability under cyclic stress	Metal/rigid scaffold replication + multilayer flexible electronics
9	Cardiovascular disease	Robot-assisted deacidifying cardiac MN	Myocardial infarction (porcine/rabbit model)	VEGF + self-propelled microrobots carrying EVs	Elastic polyurethane dual-layer flexible base	pH-triggered release (pH < 6.5) enabling targeted microrobot migration	Arrhythmia risk and full biodegradability evaluation	3D bioprinting + microfluidic robotic encapsulation
10	Neurodegenerative disease	Toothbrush-shaped nose-to-brain MOF MN	Alzheimer's disease model	CD-MOFs + Huperzine A	Toothbrush-like high-density long needle array	Intranasal axonal transport via olfactory/trigeminal pathways	Neurotoxicity and glial activation assessment	Precision molding + integrated handle assembly
11	Intestinal disease	Pufferfish-inspired barbed MN robot	Porcine intestinal absorption model	Insulin/anti-inflammatory biologics	Radially expandable biomimetic barbed structure	Peristalsis-triggered expansion and mechanical anchoring with dissolving release	Barbed tip detachment safety; obstruction/perforation risk evaluation	Soft micromechanical fabrication + secondary molding
12	Facial rejuvenation	mRNA EV intracellular collagen MN	Skin photoaging model	COL1A1 mRNA-loaded nanoporous EVs	Flexible pedestal-supported dense microarray	EV uptake-mediated intracellular collagen I synthesis	Clinical evaluation of erythema, nodules, hypersensitivity	Gradient vacuum microarray casting
13	Alopecia	Reservoir-type micelle–microsphere MN	Androgenetic alopecia model	Minoxidil + PLGA microspheres	Large-base conical array for dense hair penetration	HA burst release + long-term PLGA depot sustained release	Systemic toxicity and metabolite safety assessment	Two-step mold self-assembly filling
14	Liver disease	Dealloyed bioelectronic sensing MN	Liver fibrosis model	Au/Cu dealloyed nanostructured electrode + aptamers	Anti-slip grooved high-aspect-ratio metallic array	Non-releasing implant for electrochemical real-time metabolite sensing	Mechanical fatigue and anti-fouling macrophage resistance	Metal microfabrication + selective dealloying
15	Gynecological disease	Anti-washing cellular spheroid porous MN	Asherman's syndrome model	Endometrial stem cell spheroids + lactoferrin-GelMA	Porous interlocking sheet-like MN array	Physical niche retention of spheroids resisting menstrual flow	Endometrial regeneration and reproductive safety	Porous microstructuring + in situ cell seeding
16	Schizophrenia	Stepwise detachable dual-phase release MN	Chronic schizophrenia model	Paliperidone nanocrystals	Separable step-gradient dual-phase geometry	Immediate burst release (backplate) + long-term zero-order release (tip depot)	PLGA degradation safety and EPS incidence evaluation	Two-stage precision layered molding

3. Conclusions and future perspectives

Research summarized in this review indicates a significant evolution of MN technology, transitioning from first-generation passive systems to third-generation autonomous biointerfaces. Initially designed as minimally invasive tools to bypass the SC for enhanced transdermal delivery, MNs have developed into multifunctional platforms capable of sensing, responding to, and remodeling complex tissue microenvironments.

Across diverse disease models, MN systems act as active biochemical and biomechanical regulators. Representative advances include ferroptosis induction in fibrotic myofibroblasts, cGAS-STING pathway activation for systemic tumor immune priming, and efferocytosis enhancement for intervertebral disc regeneration. In oncology, MN-mediated immunomodulatory delivery can transform primary tumors into in situ vaccines through localized immunogenic cell death, eliciting systemic anti-tumor immunity. Similarly, peristalsis-driven intestinal microneedle robots utilize endogenous physiological forces for active tissue penetration. These examples highlight the transition of MNs from inert delivery devices to dynamic participants in biological signaling.

A recurring theme is the convergence of multimodal functionalities enabled by advanced material engineering. Stimuli-responsive matrices sensitive to pH gradients, reactive oxygen species, and enzymatic activity allow localized drug release, maximizing therapeutic efficacy while minimizing systemic toxicity. External triggers such as near-infrared irradiation, electrical fields, and ultrasound provide controllable on-demand regulation. Furthermore, the integration of biohybrid components, including engineered exosomes, live therapeutic microorganisms, and magnetically guided microrobots, defines the emerging frontier of living therapeutics, enabling synthetic systems to overcome complex delivery barriers.

3.1. Overcoming biological and immunological barriers in preclinical-to-clinical translation

3.1.1. Anatomical and biomechanical discrepancies

A major limitation in current MN research is the overreliance on small rodent models. While murine models offer logistical convenience, their skin architecture differs significantly from human skin, limiting translational relevance. Histologically, human skin possesses a thicker and mechanically more robust SC (10-20 μm) [247] and a dense, collagen-rich dermis (1.5-4.0 mm) [248], whereas murine skin has an approximately 5 μm SC and a 0.2-0.4 mm compliant dermis [249]. These structural differences alter in vivo insertion mechanics and stress distribution [250,251]. Microneedles with low polymeric Young's modulus may achieve high penetration efficiency in soft mouse skin but fail due to premature buckling or insufficient insertion depth in mechanically resistant human skin [[252], [253], [254]]. Failure to exceed the critical piercing threshold (σbuckling < σpiercing) prevents therapeutic payloads from reaching targeted vascularized dermal niches [255].

To bridge this biomechanical gap, future preclinical evaluation should adopt a tiered translational testing pipeline, progressing from rodent models to large animals (e.g., porcine or ovine skin) that more accurately recapitulate human mechanical properties. Ex vivo human skin and organ-on-chip platforms should also be integrated to establish predictive in vitro-in vivo correlations (IVIVC). Translational constraints must be incorporated early into MN design, shifting the focus from model-optimized performance to human-relevant mechanical engineering.

3.1.2. Immunological divergence and wound-healing heterogeneity

Beyond biomechanics, interspecies differences in immune microenvironments and tissue repair mechanisms pose significant translational challenges. Murine skin exhibits distinct spatial distribution, density, and receptor expression of dendritic cells and T-cell subsets compared with human skin. Local immunomodulatory strategies validated in rodents, such as regulatory T cell delivery or cGAS-STING pathway activation, may induce excessive inflammatory responses in humans.

Moreover, wound healing in mice primarily relies on myofibroblast-mediated rapid contraction, whereas humans require coordinated re-epithelialization, granulation tissue formation, and extensive ECM remodeling. Consequently, nanomaterials or cell-laden hydrogels that accelerate murine diabetic ulcer healing often fail to recapitulate the slower and more complex kinetics of human chronic wounds. To address these limitations, future research must develop human-relevant chronic wound models, including patient-derived ex vivo tissues and advanced microphysiological immune-competent frameworks capable of recapitulating human inflammatory cascades.

3.2. Engineering audit: industrial scalability, biocompatibility, and regulatory pathways

3.2.1. Manufacturing feasibility and the sterilization paradox of intelligent materials

The integration of advanced materials, including MOFs, nanozymes, AIEgens, smart hydrogels, and bio-hybrid systems, represents the current frontier of living therapeutics. However, their industrial translation is constrained by scalability and quality control. Conventional laboratory fabrication methods, such as layer-by-layer assembly and micromolding, are low-throughput and poorly compatible with commercial scale-up. Furthermore, incorporating MOFs or nanozymes can disrupt polymer matrix homogeneity, leading to aggregation and batch-to-batch variability. For biologically derived components, preserving structural integrity and bioactivity against thermal, vacuum, or shear-based processing remains challenging.

This highlights a critical gap in current MN development: the absence of a design-for-translation paradigm. Sterilization requirements further exacerbate translational barriers. Conventional terminal sterilization techniques (e.g., γ-irradiation, ethylene oxide) meet regulatory standards but frequently degrade nucleic acids, inactivate proteins, or disrupt MOF crystallinity. Conversely, aseptic manufacturing avoids payload denaturation but increases production complexity and cost. Transitioning from laboratory-scale solvent casting to industrial high-fidelity 3D printing and automated sterile manufacturing is essential for ensuring reproducibility.

3.2.2. Long-term safety and biocompatibility evaluation frameworks

As MN platforms evolve toward deep-tissue applications, acute cytocompatibility testing is insufficient. Inorganic components such as MOFs and nanozymes often contain heavy metal ions (e.g., Fe, Cu, Mn, Ce), whose clearance pathways, metabolic degradation kinetics, and long-term accumulation remain poorly understood, introducing potential risks of chronic toxicity.

For living or biologically derived carriers, immunogenicity is a major concern. Prolonged utilization may induce delayed hypersensitivity reactions or fibrotic encapsulation, which isolates MN bio-interfaces from the surrounding interstitial fluid, terminating therapeutic efficacy. Therefore, standardized long-term safety evaluation frameworks, incorporating multi-year immunotoxicity assays, precise biodistribution tracking, and quantitative degradation profiles, are essential before clinical deployment.

3.2.3. Lessons from clinically translated human MN systems

Clinically translated or advanced MN products provide invaluable empirical guidance, emphasizing that translational success depends not on maximal functional complexity, but on structural simplicity, material reliability, scalable manufacturing, and regulatory clarity.

Clinically Translated Platform	Structural/Material Paradigm	Core Engineering Insight & Clinical Contribution
BD Soluvia™	Hollow Metallic Array	Demonstrated the feasibility of precise dermal targeting, optimizing intradermal influenza vaccination with reduced patient discomfort.
MicronJet®	Silicon MN Platform	Highlighted the paramount importance of geometric precision and microfabrication reproducibility in achieving reliable fluid delivery.
Zosano Pharma M207	Titanium-Coated Patch	Successfully completed Phase III clinical trials for zolmitriptan delivery in migraine therapy, underscoring predictable transdermal flux and manufacturing consistency.
Dermaroller®/Morpheus8	Solid Mechanical Arrays	Demonstrated that controlled mechanical microinjury alone can induce dermal collagen remodeling and tissue regeneration without any pharmacological payloads.
FreeStyle Libre/Dexcom G7	Subcutaneous Biosensors	Proved the long-term feasibility, biocompatibility, and commercial scalability of MN-based continuous biosensing in human tissue.

Beyond currently marketed products, several late-stage clinical candidates merit attention for their potential to validate MN technology in new therapeutic domains. Zosano Pharma's ADAM technology (zolmitriptan MN patch, Phase III completed) demonstrated migraine relief within 30 min, representing the first MN-based CNS drug delivery platform to achieve regulatory-grade clinical endpoints [256]. In the infectious disease space, Vaxxas's high-density microarray patch (HD-MAP) for measles-rubella vaccination has entered Phase I/II trials, leveraging thermostable coating to eliminate cold-chain requirements-a critical advantage for global health deployment [257]. For diabetes management, Echo Therapeutics' Symphony tCGM system employs a biosensor-integrated MN array for continuous glucose monitoring without blood calibration, bridging the gap between intermittent monitoring and closed-loop artificial pancreas systems [258]. These candidates illustrate a deliberate industry pivot toward indication-specific MN designs rather than platform-agnostic approaches, a trend we view as essential for overcoming the translational barriers identified in preceding sections.

3.3. Outlook: the next decade of smart adaptive bio-interfaces and IoMT

Looking forward, next-generation intelligent MN platforms are expected to evolve into autonomous, cell-instructive interfaces for precise and regenerative healthcare. To achieve regulatory and commercial success, the next decade of research must prioritize five interconnected pathways:

First, the establishment of standardized IVIVC frameworks is needed to develop predictive models mapping in vitro release profiles and mechanical performance onto human in vivo outcomes.

Second, the development of smart multi-analyte closed-loop architectures must evolve beyond simple glucose-responsive systems toward complex monitoring capable of simultaneously detecting inflammatory cytokines, electrolytes, and tumor markers.

Third, integration with the Internet of Medical Things (IoMT) will transform MN patches into active nodes. This convergence with wearable electronics and AI-driven platforms will allow continuous remote monitoring and wireless on-demand dosing via external physical triggers.

Fourth, the synthesis of adaptive materials will transition toward macromolecular architectures capable of real-time molecular computation. These responsive matrices will perform logic-gate processing directly at the bio-interface in response to physiological changes.

Fifth, early-stage commercial integration requires embedding pharmacoeconomic metrics, sterilization compatibility, and regulatory-driven design principles into early engineering phases, ensuring cost-effectiveness compared with standard therapies.

By bridging the gap between solid-state materials and biological systems, these advanced arrays will shift from laboratory concepts to key technologies in precision medicine and patient-centric healthcare.

Ethics approval and consent to participate

None.

CRediT authorship contribution statement

Yiming Xiang: Data curation, Formal analysis, Funding acquisition, Investigation, Resources, Writing – original draft, Writing – review & editing. Ziya Gong: Investigation, Resources, Writing – original draft. Juying Liu: Formal analysis, Writing – original draft. Yizhou Zhu: Formal analysis, Funding acquisition, Investigation. Zhiyong Zhang: Funding acquisition, Resources, Supervision. Bin Li: Formal analysis, Funding acquisition, Supervision. Jian Luo: Data curation, Formal analysis, Funding acquisition. Meiling Su: Data curation, Formal analysis, Funding acquisition. Kelvin W.K. Yeung: Funding acquisition, Investigation, Project administration, Resources, Supervision.

Declaration of competing interest

Kelvin W. K. Yeung is an associate editor for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.