Microneedle-based drug delivery for inflammatory and immune-mediated ocular diseases: current applications and future perspectives

ABSTRACT

Inflammatory and immune-mediated ocular diseases encompass a spectrum of conditions that arise from dysregulated immune-inflammatory responses marked by a chronic clinical course, a propensity for relapse, and a tendency to cause significant ocular tissue damage, which can lead to profound impairment of visual function. Dysregulation of the balance between immune cell subpopulations is central to the pathogenesis of many of these diseases. At present, non-specific treatments such as glucocorticoids and immunosuppressants form the cornerstone of therapy for inflammatory and immune-mediated ocular diseases. However, these treatments often suffer from poor bioavailability and targeting, cumbersome or invasive administration methods, and are associated with side effects such as increased intraocular pressure (IOP), cataracts, or glaucoma with frequent administration. These limitations underscore the urgent need for alternative drug delivery methods. Microneedles have emerged as an innovative approach to ocular drug delivery, offering distinct advantages over traditional eye drops and intravitreal injections. They enhance drug penetration and targeting, provide sustained release, and may reduce unnecessary drug exposure, thus holding great promise for the treatment of inflammatory and immune-mediated ocular diseases. This review aims to shed light on the unique benefits and efficacy of microneedles as drug-delivery systems for inflammatory and immune-mediated ocular diseases, with particular attention to noninfectious uveitis, corneal inflammatory disorders, inflammation-associated corneal neovascularization, and allergic conjunctivitis. It also discusses ocular safety and toxicity, manufacturing and standardization, regulatory challenges, and future prospects of microneedle applications, providing a comprehensive overview of their potential for ocular drug delivery.

Article highlights

• Inflammatory and immune-mediated ocular diseases remain challenging to manage, with conventional therapeutic approaches posing several limitations that underscore the urgent need for innovative drug delivery platforms.

• The distinct advantages enable microneedles to overcome existing barriers, enhancing penetration, improving targeting, reducing invasiveness, and sustaining effective drug concentrations, thus offering promising potential for clinical use.

• We further introduce limitations and challenges that necessitate further development, including the need for comprehensive safety assessments, the establishment of standardized design parameters, regulatory considerations, and the enhancement of drug-delivery capabilities.

1. Introduction

Eyes are commonly regarded as immune-privileged sites, designed to shield against immunogenic inflammation (Bucher et al. 2021). Yet, there exist inflammatory and immune-mediated disorders affecting the anterior or posterior segments of the eye. Representative conditions include noninfectious uveitis, allergic conjunctivitis, and immune-mediated corneal disorders such as stromal keratitis and peripheral ulcerative keratitis. In addition, persistent ocular inflammation may contribute to pathological outcomes such as corneal neovascularization (CNV). Dysregulated immune and inflammatory responses in these conditions may result in recurrent or persistent tissue damage and ultimately impair visual function.

Topical administration of ocular medications is the preferred method of treatment, as it enhances drug targeting and reduces systemic side effects compared to systemic administration (Glover et al. 2023). Commonly used methods include eye drops and various injection techniques, such as subconjunctival, peribulbar, and intravitreal injections. Despite these options, challenges remain in achieving sufficient drug penetration, precise targeting, maintaining optimal local drug concentrations, and minimizing adverse effects (Maulvi et al. 2021; Silva-Cunha 2021). Injectable formulations offer the advantage of delivering a precise dose to specific ocular areas, making them a prominent choice for targeted drug delivery (Gupta and Yadav 2019). However, they are highly invasive and can lead to complications such as retinal detachment and intraocular infections (Thakur Singh et al. 2017). Furthermore, the financial burden of long-term treatment for chronic conditions, coupled with the complexity of repeated administration procedures, may increase the treatment burden and affect long-term disease management (Mandal et al. 2019). The limitations inherent in traditional drug delivery methods have underscored the urgent need for innovative approaches.

Microneedles are micron-scale drug-delivery devices characterized by an array of micron-sized projections mounted on a supporting base. Their customizable composition, cargo capacity, size, and shape make them particularly well-suited for targeted local ocular drug delivery. These attributes enable microneedles to overcome existing barriers, enhancing penetration, improving targeting, reducing invasiveness, and sustaining effective drug concentrations, thus offering promising potential for ocular drug delivery (Seo et al. 2020; Amani et al. 2021).

This review focuses on MN-based drug delivery for inflammatory and immune-mediated ocular diseases, with particular attention to noninfectious uveitis, corneal inflammatory disorders, inflammation-associated CNV, and allergic conjunctivitis. In addition, current challenges related to therapeutic performance, ocular safety and toxicity, manufacturing and standardization, and regulatory translation are discussed, together with future perspectives for the clinical development of ocular MN-based drug-delivery systems.

2. Challenges in the treatment of inflammatory and immune-mediated ocular diseases

Although the eye is equipped with a multitude of protective mechanisms against both exogenous and endogenous pathogens, it remains susceptible to immune-mediated diseases. Inflammatory and immune-mediated processes are recognized as leading causes of blindness, underscoring the importance of effective intervention strategies (Di Zazzo et al. 2017; Keino et al. 2018). Immunotherapies that modulate the immune system have demonstrated potential in altering the course of these diseases and providing effective management for conditions that threaten sight (Milling et al. 2017).

Various ‘classic’ drugs, including corticosteroids, immunosuppressive agents such as cyclosporine A and tacrolimus, and anti-VEGF therapy, are currently in clinical use (Teabagy et al. 2023; Wang et al. 2023). However, despite advancements in immunopharmacology, the management of immune-related ocular diseases still faces challenges, including the unpredictability of therapeutic efficacy, limited targeting capabilities, difficulties in drug tissue infiltration, and the risk of adverse reactions (Falavarjani and Nguyen 2013; Tavakoli et al. 2020). Simultaneously, given the prolonged treatment required for nearly all immune-mediated diseases, the potential monotony of the procedure and the accompanying adverse effects pose persistent challenges for patients (Kang-Mieler et al. 2020) (Figure 1). This highlights the necessity for innovation in drug delivery systems.

Figure 1.

Drawbacks of traditional therapeutic approaches. Some of the elements in illustrations are created by Figdraw.

In response to these challenges, the field of drug delivery is evolving, with a notable trend being the reduction of needle size to minimize tissue damage, reduce infection risks, and enhance overall safety, which has led to the development of microneedles (MNs) (Chiang et al. 2017a, 2017b; Gadzinski et al. 2022). The effective management of immune-related diseases is believed to hinge on the administration of optimal dosages of immunomodulators, the selection of appropriate delivery methods, and the precision of infusion site selection (Amani et al. 2021). Microneedles have emerged as a promising approach for drug administration, offering the benefits of sustained drug release, personalized dosage control, and precise targeting. Their introduction represents a significant step forward in the treatment of immune-related ocular diseases.

3. Utilization of microneedles in the field of immunotherapy

Immunotherapy is a groundbreaking therapeutic strategy that holds the potential to manage a wide array of diseases by fine-tuning the immune response of individuals (Bookstaver et al. 2018). Despite its promise, several hurdles remain to be addressed, such as the risk of off-target toxicity, the complexity of tissue heterogeneity, and the lack of durability. Microneedles, crafted from polymers or metals, have recently captured the attention of researchers in the field of immunotherapy due to their distinct advantages (Park et al. 2022) (Figure 2).

Figure 2.

Schematic of the distinct features of microneedles in immune modulation. Reproduced with permission (van der Burg et al. 2019; Wang et al. 2021). Copyright 2019, Elsevier B.V. and 2021, Springer Nature. Some of the elements in illustrations are created by Figdraw.

3.1. The distinct features of microneedles in immune modulation

3.1.1. Control the release kinetics of cargo

The precise control of immune signals and the kinetics of cargo release are essential for effective immunoregulation (Skakuj et al. 2021). One of the compelling features of microneedles (MNs) is their ability to be engineered to release cargo in various mechanisms, such as burst, sustained, or controlled release (Edwards et al. 2023).

In situations where an immediate high dose of medication is necessary to stimulate the recruitment of immune cells, a burst release mechanism is crucial. This requires the rapid availability of the drug/cargo within a short timeframe, thereby facilitating the swift generation of an immune response (Edwards et al. 2023). Bhatnagar et al. (2018) prepared a polymer microneedle capable of rapid dissolution to deliver besifloxacin. It showed that the microneedles were found to dissolve completely in the cornea within 5 min, significantly enhancing drug penetration and accumulation, and exhibiting improved antimicrobial activity. Furthermore, microneedles with slow-release properties have been shown to increase the bioavailability of many immunotherapies while simultaneously reducing the cost and risk of complications. Chen et al. (2018) illustrated that the sustained delivery of inactivated influenza viruses or OVA antigens was achieved when these viruses were loaded into soluble chitosan microneedles (up to 28 days), resulting in heightened influenza virus-specific IgG reactivity compared to intramuscular injections in mice.

The evolution of responsive microneedle systems promises to refine the precise control over the spatial and temporal release of encapsulated therapeutic agents. Wang et al. (2016) developed a biodegradable hyaluronic acid (HA) microneedle system loaded with pH-sensitive glucose nanoparticles that encapsulated anti-PD1 antibody and glucose oxidase (GOx). The acidic tumor microenvironment facilitated the auto-dissociation of the nanoparticles, leading to a substantial release of aPD1, which effectively mitigated melanoma progression (Figure 3). Delivering temperature-sensitive and biodegradable drugs, such as mRNA, in vivo presents a significant challenge that conventional microneedles cannot adequately address. To overcome this, cryo-microneedles have been introduced to meet the specific temperature-sensitive demands of active drug delivery. Yu et al. (2022) created cryo-microneedles by integrating mRNA with an HA solution. In vivo studies in mice demonstrated that these cryo-microneedles successfully induced specific immune responses, achieving comparable transfection effects to those of mRNA-loaded PEI or liposomes.

Figure 3.

Schematic diagram of the MN patch for the delivery of aPD1 in the treatment of skin cancer. (a) Schematic illustration of the microneedle patch delivery system for local aPD1 delivery to melanoma. (b) Schematic illustration of PD-1 blockade mediated by aPD1 at the T cell–cancer cell interface. Reproduced with permission (Wang et al. 2016). Copyright 2016, American Chemical Society.

3.1.2. Improve the targeting of delivery

Off-target toxicity is a significant challenge in immunotherapy, where unintended effects can complicate treatment outcomes. Microneedles, however, bring a range of distinct benefits to this field, notably increased specificity and targeted delivery of immunomodulatory cargos, as well as reduced risk of adverse reactions (Riley et al. 2019). Various studies have illustrated the capacity of microneedles to precisely deliver antigens and co-stimulatory signals to antigen-presenting cells (APCs) located at high density within the dermis of the skin. APCs, including dendritic cells (DCs), Langerhans cells (LCs), and B cells, migrate to secondary lymphoid organs (SLOs) to interact with effector T cells, thereby amplifying the immune response by enhancing the quantity and specificity of cells and antibodies combating pathogens.

Microneedles mitigate off-target effects associated with systemic administration by specifically targeting immune cells, ensuring that the cargo is primarily utilized to elicit the desired immune response, thereby maximizing the efficacy of the immune response (Tsai et al. 2020). Studies have shown that microneedle delivery significantly reduces the accumulation of therapeutic cargo in non-target tissues or organs at equivalent doses, when compared to other delivery routes such as intradermal (I.D.), subcutaneous (S.C.), or intramuscular (I.M.) administration (Kang-Mieler et al. 2020). Beyond cargo delivery, the geometry and material properties of MNs may also influence local immune-cell recruitment and distribution, further affecting the spatial specificity of immune modulation (van der Burg et al. 2019).

Owing to the distinct anatomical and physiological features of the eye, its immune system possesses specific characteristics, such as the localization of immune cells at various barrier sites (Taylor 2016). For example, the sclera is home to a substantial number of macrophages and DCs (Chinnery et al. 2017), while the conjunctiva hosts mucosa-associated tissue immune cells (Alam et al. 2020). A recent discovery revealed the presence of memory T cells in the cornea, which actively patrol and combat viral infections (Loi et al. 2022). In this study, it was observed that these memory T cells persist in the cornea following infection with herpes simplex virus, acting as a defense against potential reinfection. These findings suggest that microneedles may provide opportunities for localized therapeutic intervention within distinct ocular immune microenvironments, thereby enabling spatially controlled modulation of ocular immune responses while potentially minimizing unintended effects on non-target tissues. Importantly, MNs should not be regarded as uniformly immunostimulatory or immunosuppressive systems. Although they primarily serve as localized delivery platforms, their immunological effects are determined not only by the therapeutic cargo, target tissue, and disease context, but may also be influenced by device-related factors such as material composition, geometry, penetration depth, and mechanical micro-injury (Zeng et al. 2024).

In inflammatory and immune-mediated ocular diseases, reducing off-target exposure is particularly important because therapeutic and adverse effects may occur in anatomically distinct ocular compartments. For example, in posterior uveitis, corticosteroids are intended to suppress pathological inflammation in the choroid and retina, whereas unnecessary drug exposure to anterior ocular tissues may contribute to steroid-related adverse effects. Suprachoroidal delivery using MNs provides a compartment-specific approach that preferentially distributes therapeutic agents toward the posterior segment while limiting anterior segment exposure (Habot-Wilner et al. 2019). Pharmacokinetic studies of suprachoroidally administered triamcinolone acetonide have further demonstrated high and sustained drug levels in the chorioretina with relatively limited anterior segment exposure (Muya et al. 2022).

Conversely, for corneal inflammatory disorders, inappropriate penetration depth or unintended exposure of adjacent tissues to immunologically active cargos may potentially exacerbate inflammation. Therefore, the therapeutic benefit of ocular MNs depends not only on improving drug-delivery efficiency but also on optimizing needle geometry, penetration depth, formulation, and biocompatibility to achieve disease- and tissue-specific delivery while minimizing off-target effects.

3.1.3. Potential to reduce treatment burden and improve patient acceptability

Microneedles are often considered patient-friendly delivery systems because of their minimally invasive design in some clinical settings (Gupta and Yadav 2019). For example, in a Phase 1 influenza vaccine trial (Frew et al. 2020), 70% of participants preferred MN administration over nasal spray or intramuscular injection. However, in ophthalmology, most needle-based procedures are performed under topical or local anesthesia and are generally well tolerated. Therefore, reduced procedural discomfort alone is unlikely to represent the primary clinical advantage of ocular MNs.

Instead, the potential patient-level benefits of ocular MNs may arise from their ability to achieve localized and controlled drug delivery. Chronic inflammatory and immune-mediated ocular diseases often require prolonged treatment and repeated administration, resulting in a substantial treatment burden. The targeting and controlled-release characteristics discussed above may also have important patient-level implications. By potentially reducing unnecessary drug exposure or the frequency of repeated administration, MN-based systems may simplify long-term treatment regimens and reduce the treatment burden. Such advantages may improve patients’ willingness to continue therapy and potentially contribute to better long-term adherence and acceptability. Ocular studies demonstrating dose-sparing and localized drug delivery provide indirect support for this potential (Gilger et al. 2013; Habot-Wilner et al. 2019); however, direct clinical evidence showing superior adherence, preference, or quality of life with ocular MN-based treatment remains limited. Further prospective studies are therefore needed to determine whether the delivery advantages of MNs translate into meaningful improvements in patient experience.

3.2. MNs for immunotherapy and trends of clinical application

Microneedles have recently emerged as a compelling option for immunotherapeutic delivery, offering unique advantages that facilitate the precise elicitation of targeted immune responses through controlling the release of immunotherapeutic agents and safely delivering antigens (Han et al. 2020). For example, researchers (Chen et al. 2020) have designed hollow-structured microneedles loaded with an anti-programmed death-ligand 1 antibody (aPD-L1) and combined them with cold atmospheric plasma (CAP) therapy. This innovative approach utilizes the microneedles' hollow architecture to administer CAP transdermally, engaging with tumor tissue and triggering immunogenic cell death, a process further augmented by the localized release of aPD-L1.

The non-invasive and painless presentation of antigens using microneedles is a significant area of focus in current research. A novel painless vaccination method has been developed using dissolving microneedles loaded with Zika vaccine microparticles (MPs) (Kale et al. 2023). Studies have shown that these microneedles effectively stimulate the production of notable antibody levels and enhance the proportion of CD4⁺ and CD8⁺ cells in splenocytes and lymphocytes. Table 1 provides a synopsis of progress in utilizing microneedles for immunotherapy.

Table 1.

Advances in the application of microneedles in immunotherapy.

Microneedle materials	Loaded cargoes	Diseases involved	Conclusions	References
GelMA and PVA MN	exosomes	Achilles tendinopathy (AT)	It demonstrated the anti-inflammatory, proliferation-promoting, and degradation-inhibiting effects of EXO/MBA in Achilles tendinopathy.	Liu et al. (2021)
stainless steel MN	autoantigen	type 1 diabetes	It prolonged retention and enhanced antigen presentation.	Zhao et al. (2016)
GelMA MN	tetracycline and cytokine	periodontal diseases	The MN demonstrated the ability to inhibit proinflammatory factors while also facilitating the production of pro-regenerative signals, ultimately promoting tissue healing.	Zhang et al. (2022)
GelMA MN	purpurolide C loaded with macrophage liposomes	delayed wound healing in diabetes	The delivery system successfully penetrated the skin barrier to administer PC to local tissues, effectively modulating macrophage polarization in the treatment of diabetic wounds.	Liu et al. (2023)
PVP MN	anti-CTLA4 along with active motor-Mg microparticle	melanoma tumor	The active, degradable, and autonomous microneedle delivery systems, facilitated by the inclusion of reactive Mg microparticles, resulted in improved therapeutic outcomes for melanoma.	Lopez-Ramirez et al. (2020)
PVA MN (with programmed functions)	verteporfin and crosslinked heparin	acute wound and diabetic models	PF-MNs promoted scarless wound repair in both acute and chronic wounds, and inhibited the formation of hypertrophic scar.	Zhang et al. (2023)
HA MN	CII peptide autoantigen and rapamycin	rheumatoid arthritis	The optimized microneedles eliminated RA symptoms and inflammatory infiltrations by recruiting antigen-presenting cells, particularly Langerhans cells.	Zhao et al. (2024)
HAMA MN	Fe3O4 nanoparticles on graphene oxide nanosheets	bacterial biofilm infections (BBIs)	FGO@MN eliminated more than 95% of BBIs and validated the scavenging of refractory BBIs after 15 days.	Zhu et al. (2022)
HA and CTP MN	polymer-encapsulated Cas9 RNP targeting NLRP3 and Dex-containing polymeric nanoparticles	inflammatory skin disorders (ISDs)	The treatment with MN demonstrated efficacy in reducing skin inflammation and enhancing the effectiveness of glucocorticoid therapy in psoriasis and atopic dermatitis.	Wan et al. (2021)
PLLA MN	model antigen and precise ratios of multiple classes of TLRas	vaccine	The system activated primary antigen-presenting cells and drove the proliferation of antigen-specific T cells. The utilization of MNAs led to varied T-cell responses based on the quantity of TLRa subclasses.	Edwards et al. (2023)
Gelatin MN	imiquimod	warts	Imiquimod microneedles induced secreted embryonic alkaline phosphatase in macrophages.	Chiu et al. (2021)
pullulan MN	DOX and siPD-L1 encapsulated by pH-sensitive LPs	melanoma tumor	The Si/DOX@LRGD dMNs demonstrated superior anti-tumor efficacy compared to monotherapy with dMNs and tail intravenous injection at equivalent dosages.	Tian et al. (2023)
PVP and PVA MN	CAP and aPDL1	melanoma tumor	The hollow microneedles facilitated the transdermal delivery of cationic antimicrobial peptides (CAP) to interact with tumor tissue.	Chen et al. (2020)
PEGDA and PVA MN	gram-positive bacteria Bacillus subtilis	fungal infection	The bacteria were effectively confined within the LMNs, demonstrating potent antifungal activity.	Wang et al. (2020)
HA and PVA MN	Zika vaccine MPs	vaccine	The vaccination with MPs-loaded MNs resulted in a notable increase in antibody titers and upregulation of CD4+ and CD8+ cell surface markers.	Kale et al. (2023)
PLGA MN	a clinically available vaccine (Prevnar-13)	vaccine	A biodegradable microneedle system was developed that enabled a single insertion to achieve delayed burst release of vaccine antigens at various programmable time intervals, eliciting an immune response comparable to that induced by multiple bolus injections of the same vaccine antigens.	Tran et al. (2021)
silk MN	OVA	systemic anaphylaxis	The administration of MN immunotherapy demonstrated a greater efficacy in alleviating systemic anaphylaxis.	Zhang et al. (2023)
chitosan MN	biguanide	psoriasis	BGC-MNs demonstrated efficacy in clearing circulating cfDNA, decreasing inflammatory cytokine levels in the dermis, and exhibiting a favorable therapeutic response in psoriasis.	Liu et al. (2024)
HA MN	GOx, iron ions, and PDA	infected wounds	The MN system with favorable biocompatibility displayed exceptional antimicrobial and immunomodulatory characteristics.	Li et al. (2023)
cryo-microneedle	ovalbumin- pulsed DCs	melanoma tumors	It resulted in increased antigen-specific immune responses and inhibited tumor growth at a reduced rate.	Chang et al. (2021)
HA MN	methotrexate-loaded albumin nanoparticles	psoriasis	MN patch prevented erythema and reducted in skin thickness, thus inhibiting the progression of psoriasis.	Wang et al. (2022)

Pre-clinical studies have confirmed the potential of MNs, prompting their introduction into clinical trials. Currently, microneedle patches administering the influenza vaccine are the only ones that have reached Phase 1 clinical trials in the United States for immunotherapy and infectious disease applications. A recent Phase I study evaluated the efficacy of microneedles for delivering the Japanese encephalitis vaccine, demonstrating the safety, tolerability, and immunogenic efficacy of this approach (Iwata et al. 2022). The observed dose-sparing effect highlights the promising potential of microneedles to reduce the amount of immunogens required.

Although still in early development, the potential applications of microneedles in treating ocular diseases hold significant importance. The feasibility of robotic microneedle retinal vein cannulation was successfully confirmed in a Phase I study (Willekens et al. 2021). Table 2 summarizes representative clinical studies of MN-based drug delivery and related applications.

Table 2.

Representative clinical studies of microneedle-based drug delivery and related applications.

Pathogen	MN design	Participants	Primary readouts	Secondary readouts	Conclusions	Phase	Year	References
Japanese encephalitis virus	dissolvable microneedle patch	39	the neutralising antibody titre at day 42	the neutralising antibody titre at days 14, 21, and 189	MNA-25% resulted in elevated levels of neutralizing antibody titers compared to both MNA-10% and subcutaneous injection.	phase I	2022	Iwata et al. (2022)
pepGNP-Dengue composed of synthetic T cell-selective multi-valent DENV peptides carried on ultrasmall GNPs	Nanopass MicronJet600 microneedle	26	frequency and severity of reported local and systemic AEs at 7 and 14 days; incidence of unrecorded AEs, AESIs and SAEs; and change from baseline in laboratory safety measures.	frequency of CD8+ T cells specific to PepGNP-Dengue peptides at baseline, day 21, 35, 90, and 180, and antibody titre.	The findings demonstrate the feasibility of utilizing a synthetic nanoparticle-based peptide vaccine to effectively stimulate virus-specific CD8+ T cells.	phase I	2023	Miauton et al. (2024)
influenza vaccine antigen	dissolvable microneedle patch	100	four questionnaires on mean scores for ease of use, MNP perceived protection, MNP reliability, and MNP selection knowledge at Day 0, 8 and 28.	-	The majority of participants were accepting of IIV vaccination by MNP and had a preference for it over injection.	phase I	2020	Frew et al. (2020)
Influenza inactivated viruses	Coated microneedles	60	Fold-change of hemagllutinatioation inhibition (HAI) titers, fold-change of neuraminidase inhibition (NAI) titers, investigated 3 strains of flu virus: H1N1, H3N2, NYMC BX-51	antibody binding affinity, fold changes in cytokines/chemokines, monocytes present in blood over time, Th cells, Tf cells over time, and memory B cells	MNAs induce significantly higher HAI and NAI titers after vaccination.	phase I	2020	Rouphael et al. (2021)
mRNA-1273 vaccine	the nanoporous ceramic skin patches (npMNA)	20	the proportion of participants with an antibody booster response two weeks after vaccination; frequency and severity of local and systemic adverse reactions	SARS-CoV-2 specific T cell response after vaccination and the average amount in microgram of mRNA-1273 particles and free mRNA released from the patch	Administration of mRNA-1273 via the npMNA, although considered safe, did not induce a booster response in SARS-CoV-2 spike S1 IgG binding antibodies or an increase in interferon-γ production by spike-specific T cells.	phaseⅡ	2023	Prins et al. (2023)
ocriplasmin	custom-built microneedle with robotic assistance	4	the rate of complications during surgery and the effectiveness of cannulation	change in visual acuity, CMT and venous filling times during flu-angiography two weeks after the intervention	Using robot-assisted microneedles to cannulate retinal veins is safe and feasible.	phase I	2021	Willekens et al. (2021)
aroma cream	biodegradable hyaluronic acid MN patch	15	the L-SCORAD index	VAS for pruritus and skin dryness, skin hydration, and TEWL	The BHMN patch had a greater impact on the L-SCORAD index than the NL patch, but did not show significant improvements in other areas.	-	2022	Song et al. (2023)
TA	24 gauge intravenous branula and 30 gauge 1cc insulin syringe	60	CMT and BCVA	-	Using microneedles for SCS injection of TA, along with intravitreal injection of TA, led to better visual acuity and reduced central macular thickness compared to using TA alone, with no side effects reported.	-	2022	Nawar (2022)
TA	dissolvable microneedle patch	20	the scar volume and POSAS	-	The HTSs treated with TAC-DMNs showed a significant reduction and improvement in appearance.	-	2023	Disphanurat et al. (2023)
adalimumab	hollow microneedles	24	pain, acceptability and local tolerability	safety, pharmacokinetics and immunogenicity	Intradermal adalimumab injection with microneedles is more painful than S.C. administration, but has higher bioavailability and similar effects and safety.	-	2021	Jacobse et al. (2021)
topical tacrolimus and Mn	electronic derma pen	90	grade of repigmentation and histopathological score	-	Microneedles combined with tacrolimus was a safe and effective option in vitiligo treatment.	-	2020	Ebrahim and Albalate (2020)
corticosteroids	self-dissolvable microneedle patches	25	NAPSI score	-	It had a greater, more sustained improvement of the NAPSI score at 4 months with no severe adverse effects reported.	-	2022	Yew et al. (2022)

While these studies demonstrate the broader versatility of MNs as immunomodulatory delivery platforms, their applicability to ophthalmology must be evaluated on the basis of ocular-specific anatomical requirements and disease-specific evidence. The following section, therefore, focuses on MN systems that have been directly investigated in ocular disease models or clinical settings.

4. Applications of microneedles in inflammatory and immune-mediated ocular diseases

Effective treatment of inflammatory and immune-mediated ocular diseases depends on several key factors, including the delivery of an appropriate therapeutic dose, selection of a suitable administration route, and precise targeting of the intended ocular tissue. Microneedles, with their ability to control penetration depth and enable localized and dose-controlled drug delivery, represent a promising platform for ocular therapy (Glover et al. 2023). However, the clinical maturity of these technologies varies substantially among different ocular diseases. Current evidence spans a broad spectrum, from experimental validation in disease models to clinically implemented suprachoroidal drug-delivery systems. Among the applications discussed below, suprachoroidal corticosteroid delivery for noninfectious uveitis represents the most clinically advanced example, whereas MN-based approaches for inflammation-associated corneal neovascularization and allergic ocular diseases remain at earlier stages of development. Accordingly, the following sections discuss not only the design and therapeutic effects of representative MN systems but also their evidence level, clinical relevance, and remaining translational challenges. The representative MN-based drug-delivery systems for the inflammatory and immune-mediated ocular diseases discussed in this review are summarized in Table 3.

Table 3.

Representative microneedle-based drug-delivery systems for inflammatory and immune-mediated ocular diseases and their translational status.

Ocular disease/condition	MN type/administration route	Therapeutic cargo	Experimental/clinical model	Main findings	Evidence level	Clinical status/major limitation	References
Noninfectious uveitis	Suprachoroidal MN injection	TA	Porcine model of acute posterior uveitis	Suprachoroidal delivery of 0.2 mg TA achieved an anti-inflammatory effect comparable to 2 mg intravitreal TA, demonstrating dose-sparing potential.	Preclinical	Supports dose-sparing and targeted posterior-segment delivery; further clinical validation is required	Gilger et al. (2013)
Uveitis-associated macular edema	SCS Microinjector®; suprachoroidal administration	TA	Patients with uveitis-associated macular edema	Enables targeted delivery of corticosteroid into the suprachoroidal space	Clinical	Clinically translated; FDA-approved application for macular edema associated with uveitis	Ciulla and Yeh (2022)
Inflammation-associated corneal neovascularization	Drug-coated stainless-steel MN; intrastromal delivery	Bevacizumab	Rabbit suture-induced CNV model	Local MN delivery reduced the required drug dose while effectively inhibiting CNV compared with conventional local administration	Preclinical	Long-term corneal safety, repeated-use feasibility, and clinical effectiveness remain to be established	Kim et al. (2014)
Inflammation-associated corneal neovascularization	Double-layer dissolving MN patch	DC101 ± diclofenac	Mouse alkali burn-induced CNV model	Sequential anti-inflammatory and antiangiogenic drug release reduced CNV, with combined treatment showing greater efficacy than either agent alone.	Preclinical	Translation requires evaluation of insertion reproducibility, long-term safety, and comparative effectiveness	Than et al. (2018)
Allergic conjunctivitis	PVA/PVP dissolving MN incorporating drug-loaded spanlastics	Ketotifen fumarate	Experimental rabbit model of allergic conjunctivitis	Provided sustained drug release and reduced ocular inflammatory responses, supporting localized anti-allergic drug delivery	Preclinical	Direct ocular proof-of-concept; human efficacy, repeated-use safety, and patient acceptability remain unknown	Elhabal et al. (2025)
Allergic conjunctivitis	HPMC/PVP K90 dissolving MN incorporating cubosomes	Tacrolimus	Experimental rabbit model of allergic conjunctivitis	Enhanced corneal drug permeation, sustained tacrolimus release, and reduced inflammatory mediators and ocular inflammation	Preclinical	Clinical safety and effectiveness have not yet been established	Elhabal et al. (2026)
Sjögren's syndrome-related dry eye	ROS-responsive detachable MN patch	Cyclosporine A + EGCG	Sjögren’s syndrome-related dry eye model	Sustained release >48 h; reduced Th1/Th17/macrophage-mediated inflammation	Preclinical	Long-term safety, repeated administration, and clinical feasibility require further evaluation	Mu et al. (2025)

4.1. Noninfectious uveitis

Noninfectious uveitis (NIU) comprises a heterogeneous group of inflammatory intraocular disorders characterized by chronic or recurrent inflammation that may lead to persistent damage to the uveal tract and surrounding ocular tissues (Zhong et al. 2021). Dysregulated immune responses, particularly T-cell-mediated mechanisms, play a central role in the pathogenesis of many forms of NIU (Li et al. 2022). Pathogenic T helper 17 (Th17) cells and inflammatory cytokines are recognized for their pivotal role in initiating and perpetuating tissue inflammation (Patel and Kuchroo 2015). Corticosteroids remain a mainstay of treatment for active noninfectious uveitis and are commonly used to achieve rapid control of intraocular inflammation (Valdes and Sobrin 2020).

Despite their therapeutic benefits, corticosteroids are not without drawbacks. They can lead to serious side effects, such as increased intraocular pressure (IOP) and a high risk of cataracts and glaucoma, posing a significant challenge in ophthalmic treatment (Valdes and Sobrin 2020). Classic studies of topical corticosteroid exposure showed that approximately 4%–6% of individuals are high steroid responders, with IOP elevations greater than 15 mmHg, whereas approximately one-third exhibit moderate IOP elevations of 6–15 mmHg (Armaly 1965). The intravitreal administration of corticosteroids is widely regarded as the primary method for addressing posterior ocular inflammatory conditions. However, due to the significant degree of invasion, high-dose corticosteroids must be delivered through a single intravitreal injection to minimize the dosing frequency and enhance patient compliance. This method carries the risk of severe adverse effects, including a rise in IOP, which could potentially lead to secondary chronic open-angle glaucoma (Kiddee et al. 2013). Therefore, improving drug delivery to the eye, enhancing drug targeting, and reducing the invasiveness of therapy have become critical clinical priorities. Microneedles have shown promise in overcoming the ocular barrier, allowing for the precise delivery of corticosteroids to specific locations within the eye, which positions microneedles as a potentially efficient and effective method of drug administration, offering a valuable alternative to traditional treatment modalities.

Microneedles have also demonstrated promising therapeutic effects while minimizing drug dosages. In a study by Gilger et al. (2013), the efficacy of microneedle delivery into the suprachoroidal cavity was compared with that of traditional 27 G needle injections into the vitreous cavity for anti-inflammatory treatment in a porcine model of acute posterior uveitis. The study revealed that a microneedle-administered dose of 0.2 mg of the anti-inflammatory drug triamcinolone acetonide was as effective as a 2 mg dose delivered via 27 G needles, without any observed adverse effects such as hemorrhage, drug toxicity, or a significant increase in IOP. These findings suggest that transscleral microneedles could provide a safer and more cost-effective alternative to intravitreal injections. The XIPERE® device, which utilizes suprachoroidal space (SCS) Microinjector® technology, has been granted marketing approval as the first and only microneedle device for ocular drug administration (Ciulla and Yeh 2022). This device is specifically designed for the delivery of a triamcinolone acetonide suspension into the SCS to treat uveitis-associated macular edema (Figure 4). The SCS Microinjector® technology allows for precise targeting of the choroid and ensures a uniform distribution of the drug within the SCS, contingent upon the pressure gradient within the choroidal space (Habot-Wilner et al. 2019).

Figure 4.

Schematic illustration of Xipere microinjector® targeting suprachoroidal drug delivery. Reproduced with permission (Glover et al. 2023). Copyright 2023, Elsevier.

Collectively, these studies represent the most clinically advanced application of ocular MN-based drug delivery, demonstrating a translational pathway from experimental validation to clinical implementation of suprachoroidal corticosteroid delivery. However, further studies are needed to evaluate long-term safety, repeated administration, and comparative effectiveness in broader clinical settings.

4.2. Corneal inflammatory disorders and inflammation-associated corneal neovascularization

Corneal inflammatory disorders represent a diverse group of diseases in which dysregulated immune responses contribute to epithelial barrier disruption, stromal inflammation, tissue remodeling, and visual impairment. Herpetic stromal keratitis (HSK) is a representative example, where corneal injury results not only from the initial viral infection but also from persistent host immune responses. The infiltration of inflammatory cells and the release of cytokines and other inflammatory mediators contribute to stromal damage, corneal scarring, and pathological neovascularization (Wang et al. 2020). Peripheral ulcerative keratitis (PUK) is another severe inflammatory corneal disorder characterized by progressive peripheral stromal thinning and ulceration. It may occur in association with ocular inflammatory diseases or systemic autoimmune and vasculitic disorders, involving both cellular and humoral immune mechanisms in corneal tissue destruction (Hassanpour et al. 2022). Under these conditions, achieving effective suppression of inflammation while preserving corneal structure and function remains a major therapeutic goal.

These inflammatory characteristics highlight the need for localized therapeutic strategies capable of achieving sufficient drug concentrations within the cornea while minimizing unnecessary exposure to surrounding tissues. MN-based delivery may provide a potential approach by enabling controlled deposition of anti-inflammatory or immunomodulatory agents into specific corneal layers.

Beyond direct tissue damage, persistent stromal inflammation may also promote pathological angiogenesis, making corneal neovascularization (CNV) an important complication associated with various inflammatory corneal conditions. CNV is a complex pathological process with diverse etiologies, including inflammation, infection, trauma, and other ocular surface disorders (Nicholas and Mysore 2021). In inflammation-associated CNV, an imbalance between pro-angiogenic and anti-angiogenic signals, together with inflammatory cell infiltration and macrophage polarization changes, contributes to disease progression (Yang et al. 2016; Fu and Xin 2019; Droho et al. 2023). Therefore, localized delivery of anti-inflammatory and antiangiogenic agents to the corneal stroma represents an attractive strategy for controlling both inflammatory responses and pathological vascular growth.

Corticosteroids have long been used in the management of inflammation-associated CNV by suppressing inflammatory-cell infiltration and angiogenic signaling (Roshandel et al. 2018; Gaballa et al. 2021). Corticosteroids may also inhibit VEGF-related pathways and thereby reduce pathological angiogenesis. However, prolonged corticosteroid treatment is associated with treatment-related adverse effects and may increase the burden of long-term therapy. In light of these limitations, microneedles have emerged as a promising minimally invasive approach for localized corneal drug delivery. Kim et al. (2014) coated bevacizumab onto the surface of stainless-steel microneedles with a length of approximately 400 μm to deliver the drug in a minimally invasive manner to the corneal stroma. Compared with topical eye drops and subconjunctival injections, the use of microneedles resulted in significant reductions in drug dosage while achieving a more pronounced therapeutic effect, effectively inhibiting corneal neovascularization. This method not only minimizes drug dosage but also potentially mitigates the occurrence of adverse events associated with prolonged topical bevacizumab administration. A preliminary safety evaluation of the microneedles in this study determined that they were well-tolerated by the cornea, indicating promising clinical implications.

Microneedles with a two-layer structure provide an innovative approach to drug delivery, enabling a rapid initial achievement of effective drug concentrations coupled with a sustained, slow release (Figure 5). Than et al. (2018) developed a microneedle ophthalmic patch with a two-layer design for treating corneal neovascularization. The inner layer of the patch, made from HA, is engineered to dissolve quickly upon contact with tissue fluids, leading to an immediate release of the drug. In contrast, the outer layer, crafted from cross-linked methacrylic acid hyaluronic acid (MeHA), is formulated to resist dissolution, ensuring the gradual release of the drug over time. This dual-layer design results in a controlled two-stage drug-release profile. These findings indicated that the administration of an anti-VEGFR2 drug (DC101) through these microneedles effectively reduced the corneal neovascularization area and exhibited substantial therapeutic efficacy in a murine disease model. Building on this, the researchers further explored the use of microneedles to load two distinct drugs: a nonsteroidal anti-inflammatory drug (diclofenac) in the fast-dissolving HA layer, and DC101 in the slow-dissolving, cross-linked MeHA layer. This dual-drug loading strategy allowed for a sequential release of the medications, and the combined administration of these two drugs showed a more pronounced therapeutic effect than the administration of either drug alone, suggesting the potential broad utility of the two-layer structured microneedles.

Figure 5.

Schematic illustration. Fabrication process of the polymeric patch with an array of double-layered micro-drug-reservoirs. Reproduced with permission (Than et al. 2018). Copyright 2018, Springer Nature.

Although these studies demonstrate the feasibility of localized and sequential drug delivery to the cornea, current evidence remains predominantly preclinical. Further studies are required to determine long-term corneal safety, insertion reproducibility, repeated-use feasibility, and therapeutic efficacy across different inflammatory corneal conditions.

4.3. Allergic conjunctivitis

Allergic conjunctivitis (AC) is an immunologically mediated allergic condition, hallmarked by symptoms such as ocular itching, redness, and swelling, with potential complications such as keratitis that can result in irreversible damage to vision (Miyazaki et al. 2020). During the immune response, allergens are captured by APCs and presented to naïve CD4⁺ T cells within the lymph nodes. This process triggers the differentiation of T cells into Th2 cells, which in turn stimulate B cells to produce specific immunoglobulin E (sIgE) (Paris et al. 2021). sIgE plays a key role in allergic responses by binding to high-affinity receptors on mast cells (MCs) and basophils (Brown et al. 2008). Upon re-exposure to the allergen, cross-linking of receptor-bound IgE activates these cells, leading to the release of histamine and other inflammatory mediators (Paris et al. 2023). The current clinical management of AC is primarily focused on allergen avoidance or symptomatic relief through medications, including antihistamines and corticosteroids. However, avoiding allergens such as pollen or dust can be extremely challenging, and their presence can significantly impair the quality of life for patients with AC.

Recent studies have provided evidence supporting the potential application of MN-based delivery systems in allergic conjunctivitis. Elhabal et al. developed polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP) dissolving MNs incorporating ketotifen fumarate-loaded Spanlastics to enhance local drug deposition and prolong drug release (Figure 6). The system achieved sustained ketotifen release for up to 72 h in vitro. In an ovalbumin/aluminum hydroxide-induced rabbit model of allergic conjunctivitis, MN administration alleviated ocular inflammatory manifestations and reduced the levels of IgE, TNF-α, and IL-6 (Elhabal et al. 2025). These findings suggest that dissolving MNs may improve the local availability and therapeutic duration of anti-allergic agents.

Figure 6.

Illustration of KF-SP-loaded PVA/PVP dissolving microneedle patch for the treatment of allergic conjunctivitis. Reproduced with permission (Elhabal et al. 2025). Copyright 2025, Springer Nature.

More recently, a dissolving HPMC/PVP K90 MN system incorporating tacrolimus-loaded cubosomes was evaluated for allergic conjunctivitis treatment. This system exhibited efficient insertion and sustained tacrolimus release, while ex vivo experiments demonstrated enhanced corneal drug permeation compared with that of conventional tacrolimus suspension. In a rabbit model, MN-mediated tacrolimus delivery reduced ocular inflammatory responses, accompanied by decreased levels of TNF-α, IL-1β, IL-6, and NLRP3, with histopathological evaluation showing no obvious signs of ocular irritation (Elhabal et al. 2026). Together, these studies suggest that MNs may facilitate the local delivery of both conventional anti-allergic agents and immunomodulatory drugs with limited ocular bioavailability.

Beyond allergic conjunctivitis, MN-based systems have also been explored for other immune-mediated ocular surface disorders. Recently, Mu et al. developed a ROS-responsive detachable MN patch for Sjögren’s syndrome-related dry eye, enabling peri-lacrimal gland delivery of cyclosporine A and epigallocatechin gallate. The system achieved sustained drug release for more than 48 h and reduced ocular inflammation by modulating ROS levels and suppressing Th1 and Th17 responses in a dry-eye model (Mu et al. 2025). This study further highlights the potential of MN platforms for targeting immune-related ocular tissues beyond conventional ocular surface administration.

Nevertheless, several challenges remain before MN-based approaches can be widely applied in allergic conjunctivitis and other immune-mediated ocular surface disorders, including optimization of penetration depth, consistency of insertion into superficial ocular tissues, effects of blinking and tear-film dynamics, repeated-use safety, sterility, patient comfort, and potential epithelial injury.

5. Discussion and current challenges

The studies discussed in this review highlight the potential of MN-based platforms to address several limitations of conventional ocular drug delivery, including restricted tissue penetration, limited drug retention, and the challenges associated with frequent administration. Depending on the design and target tissue, MN systems may enable localized drug deposition, tunable penetration depth, and sustained or sequential release profiles. However, the translational progress of these technologies remains uneven among different ocular diseases. Currently, suprachoroidal corticosteroid delivery represents the most clinically advanced example of MN-assisted ocular therapy, whereas MN applications for treating corneal inflammatory diseases and allergic conjunctivitis are still largely restricted to preclinical studies.

Importantly, the potential advantages of MNs should be considered in relation to existing ocular drug-delivery modalities. Rather than replacing conventional eye drops, periocular injections, or intravitreal administration, MNs may offer particular benefits in situations where current strategies are limited by insufficient tissue penetration, off-target exposure, or the need for frequent administration (Kim et al. 2014; Li et al. 2026). The clinical relevance of these advantages will ultimately depend on whether MN-based delivery can achieve improved therapeutic outcomes, safety profiles, dosing intervals, or tissue selectivity compared with established treatment approaches.

5.1. Therapeutic performance and translational challenges

Employing designed microneedles to enhance delivery efficiency is a highly promising strategy in drug administration; however, challenges remain to be addressed. Specifically, the nanoscale nature of microneedle tips necessitates enhanced drug-loading efficiency to ensure optimal therapeutic outcomes. While existing research has established that microneedle delivery can reduce the required drug dosages significantly without compromising efficacy, enhancing the drug-loading capacity of microneedles is an ongoing concern (Lopez-Ramirez et al. 2020; Zhang et al. 2022; Zhao et al. 2024). Further studies are essential to refine the design and geometry of microneedles, with a focus on increasing the volume of dissolvable microneedles or expanding the surface area of coated microneedles. In addition, dissolvable microneedles have emerged as a leading option in ocular microneedle research because of their superior ocular comfort (Glover et al. 2023). However, it is crucial to consider the effects of operational factors such as UV irradiation and repeated freezing and thawing on the bioactivity of the payloads during the preparation and encapsulation process.

Moreover, the use of desiccants is indispensable for preserving the mechanical stability of dissolvable or moisture-sensitive microneedles during transportation, thereby resulting in increased costs (Edwards et al. 2023). Additionally, the lack of established standards and regulatory processes for ensuring the accurate delivery of cargo to the target site poses challenges, particularly in the context of patient self-management (Norman et al. 2014).

5.2. Safety and ocular toxicity

Microneedles have been extensively studied for transdermal applications over an extended period of time (Nazary Abrbekoh et al. 2022). Previous studies have indicated that the repeated use of microneedles may affect the skin barrier and may be associated with local reactions such as erythema and potential infection risks. However, the safety implications of microneedle use in the delicate eye areas remain largely unexplored, and it remains to be seen whether the damage and polymer residue caused by the long-term use of microneedles can induce infections. Additionally, while localized wipes of alcohol can effectively sterilize traditional ocular treatment needles, ensuring the sterility of nanoscale microneedle arrays poses a unique challenge. High temperatures or ultraviolet irradiation could potentially affect the stability of the microneedles, thereby hindering their clinical translation. Moreover, while excipients can improve the stability of microneedle vaccines, they might also have inherent immunogenic properties that require careful consideration. Consequently, optimizing the specificity of microneedle immunotherapy through improvements in formulation and preparation techniques necessitates further refinement.

For ocular applications, potential toxicity should be evaluated in a tissue- and route-specific manner (Gadzinski et al. 2022). Unlike transdermal applications, ocular tissues have unique anatomical and biomechanical characteristics, and inappropriate penetration depth or repeated insertion may cause mechanical injury to the corneal epithelium, stroma, conjunctiva, or sclera (Mulkutkar et al. 2024). The required penetration depth varies according to the target tissue; for example, intrastromal corneal delivery requires controlled penetration into the corneal stroma, whereas suprachoroidal delivery requires precise scleral penetration. Previous studies have demonstrated that ocular MN systems with controlled dimensions can achieve targeted delivery. For instance, bevacizumab-coated stainless-steel MNs (~400 μm in length) enabled intrastromal delivery for corneal neovascularization with no apparent corneal toxicity in preliminary safety evaluations (Kim et al. 2014). However, the long-term effects of repeated administration on tissue integrity, wound healing, and ocular biomechanics remain insufficiently characterized.

Material-related safety is another important consideration, particularly for dissolving MN systems. Commonly used polymers, including HA, PVA, and PVP, are generally considered biocompatible and have been widely applied in ocular drug delivery. Nevertheless, incomplete dissolution, polymer residues, degradation products, and their potential effects on local tissue responses require further evaluation, especially for repeated administration (Short 2008). In addition, the highly localized drug deposition achieved by MNs may lead to excessive local drug exposure if drug loading or release kinetics are not appropriately optimized. Therefore, future safety assessments should consider tissue integrity, inflammation, cytotoxicity, wound healing, and long-term repeated-use safety rather than relying only on short-term ocular tolerability.

5.3. Standardization, manufacturing, and regulatory challenges

The absence of standardized guidelines for microneedle parameters presents a substantial obstacle to the clinical applications of ocular immunological therapies. Factors such as the material composition, geometry, and sharpness of the microneedle impact its puncturing capability, making these design considerations crucial for reducing invasiveness (Glover et al. 2023). Unlike transdermal applications, the intricate biomechanical environment of the eye necessitates distinct application requirements at various locations, including the conjunctiva, cornea, and sclera. For anterior segment diseases, the innovative use of contact lenses with dissolvable microneedles could potentially increase patient comfort and compliance, reducing the risk of irritation and tissue damage (Roy et al. 2020). In contrast, for posterior segment diseases such as noninfectious uveitis, coated or hollow microneedles provide the benefits of precise targeting and customizable dosing, along with adequate mechanical strength and stability, albeit at the expense of heightened tip breakage risk (Gade et al. 2024).

Concurrently, the efficacy of microneedle insertion is influenced by the size of the patch, while the limited surface area of ocular tissues (<200 mm²) poses challenges for microneedle delivery (Juliszewski et al. 2016). Additionally, the biomechanical characteristics of ocular tissues are known to vary with age and in the presence of different disease states (Blackburn et al. 2019; Boote et al. 2020). Consequently, the design of microneedles must take into account multiple factors to mitigate potential risks of injury and adverse effects in diverse clinical settings.

Clinical translation of ocular MNs requires not only therapeutic validation but also the establishment of standardized and scalable manufacturing processes. Key parameters, including needle geometry, mechanical strength, drug loading, dose uniformity, release behavior, and insertion performance, need to be consistently controlled to ensure reproducibility between batches. This challenge is particularly relevant for dissolving, coated, and multilayer MN systems, in which small variations in polymer composition, coating thickness, or fabrication conditions may affect the mechanical properties and drug-delivery performance (Mulkutkar et al. 2024). In addition, sterilization and storage conditions require careful optimization, as they may influence polymer integrity, drug stability, and overall device performance. Similar challenges related to manufacturing scalability and batch-to-batch reproducibility have also been recognized for other advanced drug-delivery platforms (Quan et al. 2026).

Beyond manufacturing challenges, regulatory translation represents another important barrier for the clinical adoption of ocular MN systems. Many drug-loaded MN platforms can be considered combination products because they integrate a therapeutic agent with a delivery device. Consequently, their evaluation requires simultaneous consideration of pharmaceutical properties and device-related characteristics, including drug quality, mechanical performance, sterility, safety, and drug–device compatibility. Furthermore, regulatory classification and approval pathways may vary among regions, while standardized regulatory frameworks specifically developed for MN-based systems remain limited. Therefore, early consideration of regulatory requirements and quality-control strategies will be essential to facilitate the successful translation of ocular MN technologies into clinical practice.

6. Future perspectives and conclusions

Future studies on ocular MN systems should focus less on demonstrating device feasibility alone and place greater emphasis on understanding how these platforms can address specific therapeutic challenges in different ocular diseases. The unique anatomical and biomechanical properties of ocular tissues, including the cornea, conjunctiva, sclera, suprachoroidal space, and posterior segment, create distinct barriers for drug delivery. Therefore, MN systems may need to be individually optimized rather than developed as a universal delivery strategy. Factors such as the target tissue, drug characteristics, required penetration depth, and release kinetics should be considered during MN design. For example, dissolving or multilayer MNs may be advantageous for anterior segment disorders requiring local and sustained drug exposure, whereas hollow or coated MNs may provide better control for delivering therapeutics to deeper ocular compartments.

An emerging direction in this field is the development of MN platforms that provide functions beyond simple drug administration, including sustained release, sequential delivery, and combination therapy. These strategies may be particularly relevant for inflammatory and immune-mediated ocular diseases, where disease progression often involves complex interactions among multiple immune pathways. Nevertheless, increased structural complexity does not necessarily translate into improved clinical performance. Future investigations should therefore clarify whether these advanced MN designs provide practical advantages over existing treatment modalities.

Despite promising preclinical findings, several challenges remain before ocular MN technologies can achieve broader clinical application. These include not only therapeutic efficacy but also reproducible manufacturing, sterilization, storage stability, ease of administration, regulatory considerations, and long-term ocular compatibility. In particular, pharmacokinetic improvements observed in experimental models need to be carefully evaluated to determine whether they result in clinically meaningful improvements in patients.

Overall, ocular MN systems represent a promising strategy to address some of the limitations of conventional ocular drug delivery. Future studies should focus on determining where MN-based approaches can provide meaningful clinical benefits, particularly in terms of tissue targeting, dosing efficiency, safety, and treatment burden in inflammatory and immune-mediated ocular diseases.

Funding Statement

This work was supported by the National Natural Science Foundation of China (Nos: 82471053, 82501270), Tianjin Natural Science Foundation (No: 24JCQNJC02050), and the Tianjin Municipal Science and Technology Program (No: 22JCZDJC00260).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

No data were used for the research described in the article.