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. 2026 Jul 10;18(28):38361–38374. doi: 10.1021/acsami.6c02463

Photothermal-Chemotherapeutic Microneedle Patch Coloaded with HMnO2 and DOX for Postoperative Management of Melanoma

Xuewei Zhang †, Yixun Zhang †, Lujia Mao †,‡, Xin Zhou †,‡, Jie Huang †, Deni Kang †, Sirong Liu †, Mingjuan Chen †, Ronghua Yang †,‡,*
PMCID: PMC13397482  PMID: 42430260

Abstract

Surgical resection remains the primary mode of treatment for melanoma. However, postoperative tumor recurrence and impaired wound healing significantly compromise the patient prognosis. In this study, we developed a microneedle (MN) patch coloaded with HMnO2 and hydroxydaunorubicin (DOX) for the simultaneous management of residual disease and postsurgical wound repair. The MN patch enables efficient transdermal delivery of both agents by penetrating the stratum corneum and targeting the surgical site. Upon near-infrared (NIR) irradiation, HMnO2 mediates photothermal ablation (PTT), effectively ablating residual melanoma cells while DOX suppresses the proliferation of potential micrometastases. Furthermore, the HMnO2/DOX@MN system modulates the local inflammatory microenvironment, promotes angiogenesis, and enhances collagen deposition, thereby accelerating the wound healing. In vivo studies using a murine melanoma model demonstrated that the MN patch significantly reduced postoperative tumor recurrence and improved wound closure rates. This multifunctional microneedle platform presents a promising strategy for integrated postoperative management, following melanoma resection.

Keywords: melanoma, microneedle patch, postoperative management, photothermal ablation, hydroxydaunorubicin, wound healing

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Introduction

Malignant melanoma represents one of the most aggressive and life-threatening forms of skin cancer. The disease is characterized by a poor prognosis and high mortality rate, largely due to its pronounced invasiveness, propensity for metastasis, and frequent recurrence. , Despite advances in oncology, the precise etiological mechanisms underlying melanoma development remain incompletely elucidated. Current evidence indicates that, against a background of genetic predisposition, melanocytes may undergo malignant transformation following prolonged exposure to ultraviolet radiation, chronic mechanical irritation, or trauma-induced stimuli, ultimately culminating in tumorigenesis. , At present, surgical resection constitutes the primary therapeutic approach for localized melanoma. Although this intervention is effective in achieving tumor control, it is associated with several postoperative challenges. − First, to reduce the risk of local recurrence, wide excision margins are typically required, resulting in extensive tissue loss, deep wound defects, and significant surgical morbidity. These factors can impair wound healing and predispose patients to complications such as hypertrophic scarring. , Second, the melanoma microenvironment is frequently immunosuppressive. In anatomically complex or highly invasive cases, such as vulvar melanoma, achieving a complete surgical resection may be challenging. Residual tumor cells can further inhibit immune surveillance, and compromised immune function, in turn, may delay tissue repair and increase susceptibility to infection.

Previous studies have demonstrated that advanced wound dressings, including composite hydrogels, fibrous membranes, and bioactive glass nanoparticles, exhibit considerable potential in promoting wound healing after skin tumor surgery. , These materials typically utilize photothermal effects to eliminate residual tumor cells while capitalizing on their inherent biological activities to facilitate tissue regeneration. However, dressings relying solely on photothermal therapy are often inadequate for eradicating tumor cells located in deeper tissue layers, thereby limiting their efficacy in preventing tumor recurrence and metastasis. Furthermore, hypoxia within the tumor microenvironment may not only promote tumor progression but also impair wound healing by prolonging the inflammatory phase.

Traditional dressings employed in clinical practice (e.g., gauze, silicone dressings) primarily focus on providing physical protection to the wound surface and absorbing exudates. , However, their efficacy in inhibiting the scar formation remains relatively limited. Following melanoma surgery, the wound site often exhibits excessive fibrous tissue proliferation. Traditional dressings fail to effectively suppress abnormal collagen deposition, thereby impairing wound healing and leading to the development of hypertrophic scars or keloids. Although some dressings incorporate antiscar agents (e.g., silicone, glucocorticoids − ), the release of these drugs frequently lacks controllability, potentially resulting in excessively high or low local drug concentrations that compromise therapeutic efficacy. − Additionally, the timeliness and specificity of drug release are insufficient, making it challenging to meet the long-term requirements of wound repair. Furthermore, real-time monitoring of wound-healing progress, feedback on wound conditions, and formulation of personalized treatment plans based on individual patient differences remain unattainable, contributing to inconsistent treatment outcomes.

Hydrogels, characterized by a high water content, excellent biocompatibility, and controllable properties, have garnered significant attention in the field of wound healing. Their unique physicochemical properties enable them to mimic the extracellular matrix (ECM), creating an optimal microenvironment for the cell growth and tissue regeneration. Researchers worldwide have developed multifunctional hydrogels by incorporating natural antibacterial components (e.g., chitosan, tannic acid) − or metal ions (e.g., silver ions, zinc ions), − endowing them with antibacterial capabilities. Substantial advancements have been made in responsive hydrogels triggered by pH, temperature, and redox stimuli. Several studies have explored integrating growth factors (e.g., VEGF, EGF) − or stem cells into hydrogels to further enhance wound-healing efficacy. For instance, Phem et al. reported the development of a thermoresponsive injectable chitosan-pluronic P123 hydrogel loaded with curcumin and gelatin (CP/Cur/Gel) for promoting wound healing and reducing scar formation. Huang et al. synthesized a self-healing hydrogel using polypyrrole nanowires coated with quaternary ammonium salt chitosan, oxidized dextran, tobramycin, and polydopamine. Xu et al. encapsulated human umbilical cord mesenchymal stem cells (hUCMSCs) within an injectable thermosensitive hydrogel composed of chitosan/sodium glycerophosphate/cellulose nanocrystals (CS/GP/CNC). This stem-cell-loaded hydrogel facilitated wound healing, re-epithelialization, keratinocyte maturation, collagen deposition, hair follicle formation, and epidermal/dermal remodeling while suppressing inflammation. Despite these advancements, most hydrogel dressings still exhibit notable limitations in terms of their therapeutic efficacy. On the one hand, mismatches between hydrogel degradation rates and the wound-healing process may lead to premature degradation or residue accumulation, impacting therapeutic outcomes. On the other hand, frequent dressing changes increase the patient burden and infection risks. Consequently, there is a pressing need to develop multifunctional wound dressings that can simultaneously eliminate residual tumor cells, modulate immune responses, accelerate wound repair, and prevent hypertrophic scar formation, thereby enabling a comprehensive adjuvant therapy after melanoma surgery.

The present study aims to achieve a dual objective: eradicating residual cancer cells following melanoma surgery and facilitating an effective wound healing and repair. Compared with traditional patches or needles, MNs are characterized by microneedle tips mounted on a supporting matrix, offering a painless, noninvasive, and convenient approach that can bypass the skin barrier for efficient transdermal drug delivery. − Specifically, by precisely tailoring template parameters (e.g., needle array arrangement, needle density, length, diameter, as well as tip and substrate morphologies), nanoparticles with distinct macro- and microstructural features can be fabricated. − Additionally, through the careful selection of functional materials for the matrix and needle tips, MNs can mediate photothermal therapy, modulate oxidative stress, exert antioxidant and antibacterial effects, and even possess hemostatic capabilities. − Manganese is an essential trace element in the human body, playing a crucial role in maintaining normal nervous system function , and regulating tumor immunity. Manganese-based metal–organic frameworks have emerged as a highly promising research area owing to their high drug-loading capacity, adaptive structures, and unique responsiveness to the tumor microenvironment (TME). , In recent years, the immune-enhancing effects of certain chemotherapeutic agents have also been validated. DOX, an antitumor antibiotic, inhibits RNA and DNA synthesis and exhibits broad-spectrum antitumor activity against various malignancies. As a nonspecific chemotherapeutic drug, DOX can eliminate tumor cells throughout the entire cell cycle.

In summary, this project design combines the HMnO2 nanostructure with the chemotherapy drug DOX and integrates it into a biocompatible, detachable MN system. Soluble dextran (Dex) is selected as the substrate for preparing the microneedle system, and methacryloacrylamide (SFMA) is used as the needle tip material. After the microneedle acts on the postoperative tumor wound, the Dex matrix dissolves rapidly and the SFMA tip (loaded with HMnO2/DOX) is embedded in the wound, which not only prolongs the interaction time but also enables DOX and HMnO2 to be effectively delivered to the tumor cells. Moreover, under acidic conditions and external light/heat stimulation, Mn2+ and chemotherapy drugs are rapidly degraded and released in large quantities through the microneedle system. Ultimately, it can inhibit the proliferation of tumor cells, induce cell apoptosis, alleviate tissue hypoxia, improve the tumor microenvironment, and enhance immune response, thereby effectively preventing local recurrence of melanoma after surgery and promoting wound healing and repair.

Materials and Methods

Materials

Soluble dextran (Dex, Mw = 70 000) was purchased from J&K Scientific Ltd., China. DOX and glycidyl methacrylate were procured from Maclean Biochemical Technology Co., Ltd. Potassium permanganate and doxorubicin hydrochloride were obtained from Aladdin Biochemical Technology (Shanghai, China). Lithium phenyl-2,4,6-trimethylbenzoylphosphonate (LAP) was acquired from Jiangyin Siteyi Biotechnology Co., Ltd. The cocoons were provided by the Zhejiang University.

Preparation of Nanomaterials

A mixture of 14 mL anhydrous ethanol, 2 mL water, and 0.5 mL of 25% aqueous ammonia solution was prepared and stirred at 50 °C for 5 min. Subsequently, 0.5 mL of tetraethyl orthosilicate (TEOS) was added dropwise, followed by continuous stirring at 50 °C for 2 h. The resulting silica nanoparticles (sSiO2 NPs) were collected by centrifugation and washed twice with a mixture of ethanol and water, then resuspended in 10 mL of water. Next, a solution of 600 mg potassium permanganate in 20 mL of water was added dropwise to the sSiO2 NP suspension, followed by ultrasonication for 1 h and stirring overnight at room temperature. The obtained SiO2@MnO2 composite was washed three times with deionized water and centrifuged at 14,800 rpm. The purified product was then dispersed in 2 mL of ultrapure water and added dropwise to a preheated (60 °C, 5 min) 2 M sodium carbonate solution (20 mL), followed by stirring for 12 h to yield mesoporous hollow MnO2 (HMnO2). The final product was washed with ultrapure water and recovered via centrifugation at 12,000 rpm.

Synthesis of Methylacrylated Silk Fibroin Protein (SFMA)

Silkworm cocoons (30 g, pupa/impurity-removed and cut into pieces) were boiled in 0.05 M sodium carbonate solution (5.3 g/1 L deionized water) for 30 min, rinsed thoroughly, and degummed twice more until boiling water no longer yellowed. Degummed silk fibroin was oven-dried. A solution was prepared by adding 40.36 g of lithium bromide (hygroscopic, quick operation) and 0.24 g of NaOH to 50 mL of deionized water (stirred, exothermic). Dried silk fibroin (10 g) was dissolved in the hot solution with stirring at 60 °C for 4 h. After neutralization with 0.5 mL concentrated HCl, 6 mL of glycidyl methacrylate was added and stirred at room temperature for 6 h. The reaction solution was filtered, dialyzed against deionized water for 3–5 days (1.2–1.4 kDa cellulose bag) to remove salts, centrifuged at 5000 rpm for 10 min, and the supernatant freeze-dried.

Characterization

A series of DOX solutions with different concentrations (3.9, 7.8, 15.6, 31.26, 62.5, and 125 μg/mL) were prepared. The full spectrum of DOX was measured by an UV–vis spectrophotometer, with fixed-point absorbance measurement at 480 nm, and the linear equation was calculated. HMnO2/DOX and HMnO2 were dropped onto copper mesh; after complete drying, their morphological structures were observed by TEM.

In Vitro Oxygen Generation Assay

The in vitro oxygen-generating capacity of HMnO2/DOX@MN was quantitatively evaluated under different pH conditions in the presence of H2O2. Briefly, HMnO2/DOX@MN, HMnO2@MN, or blank MN samples with equivalent mass were separately immersed in PBS buffer at pH 5.5 or pH 7.4. Subsequently, H2O2 was added to each sample to initiate the catalytic reaction. The dissolved oxygen concentration was continuously recorded at predetermined time points using a dissolved oxygen meter. The oxygen generation profiles were plotted as dissolved O2 concentration versus time. All measurements were performed in triplicate, and the results are presented as mean ± SD.

Drug Release

1.0 mL of 1.0 mg/mL HMnO2/DOX was added to a 1000 kDa dialysis bag, placed in a 15 mL centrifuge tube, and 3 mL of 0.1 M PBS (pH 7.4 or 5.5) was added for drug release at 150 rpm. At regular intervals, 1 mL of dialysate was taken for testing and immediately supplemented with 1 mL of fresh PBS to maintain volume. After 72 h of release, the drug release amount was determined by a UV–visible spectrophotometer. For the NIR group, samples were irradiated with 1.5 W/cm2 light for 5 min every 24 h.

Hemolysis Test

Prepare HMnO2 solutions with different final concentrations (200, 100, 50, 25 μg/mL; final volume 4 mL) in 5 mL EP tubes. Add 0.2 mL 4% red blood cell suspension, incubate at 37 °C. At 0.5, 1, 2, 3, 5, 7, 12, and 24 h, take 0.4 mL sample for centrifugation, then measure absorbance at 545 nm. Record absorbance of sample (Ai), negative control (An), and positive control (Ap); set negative, positive and blank controls simultaneously. Hemolysis rate: (Ai–An)/(Ap–An) × 100%.

Photothermal Effect

Prepare HMnO2 aqueous solutions (0, 50, 100, 200 μg/mL), add 200 μL each to a 96-well plate, irradiate the sample surface uniformly, and record temperature every 10s for 5 min with a sensor.

Hydrogel Material Characterization

Weigh 3–5 mg samples, dissolve in deuterated water, determine NMR structure at room temperature, and analyze spectra with MestReNova. FT-IR: Mix 3–5 mg samples with KBr (∼5% mass ratio), press into tablets (20 mmHg, 5 min) for detection. Rheology: Use 25 mm stainless steel parallel plate; perform dynamic strain scans (0.1–10 rad/s, RT) to determine hydrogel’s linear viscoelastic range and record G’ and G’’ curves. Compressive modulus: Compress cylindrical samples with universal testing machine to break, record breaking force; compressive strength (Pa) = F/S (F: real-time stress; S: cross-sectional area). Water absorption (Q): Cross-link 400 μL hydrogel in cylindrical mold, weigh dry weight (W dry); immerse in 37 °C PBS (pH 7.4), blot and weigh (W swollen) at set times; Q = [(W swollen – W dry)/W dry] × 100%. Degradation: Freeze-dry swollen hydrogel (W 0); immerse in PBS, incubate at 37 °C, 70 rpm; wash, freeze-dry and weigh (W t) at set times.

Microneedle Characterization

Observe morphologies of prepared MN and HMnO2/DOX MN patches by optical and scanning electron microscopy. Test mechanical properties of MN tips using an electronic universal testing machine (BOSE, ElectroForce 3220). Evaluate MN skin penetration on full-layer pigskin and observe subcutaneous drug release via laser confocal fluorescence microscopy. Due to poor pigskin light transmission, use AGAR to simulate isolated skin for observing drug diffusion and MN delivery depth. For photothermal testing of MN patches: Irradiate central part of SFMA hydrogel MN (with/without HMnO2) with 808 nm laser (1.5 W/cm2) for 5 min; record real-time temperature every 10 s and capture thermal images every minute during heating.

Cell Proliferation Assay

A375, B16F10 melanoma cells, and HSF cells (Xiamen Immocell Biotechnology Co., Ltd., China) were cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (P/S). Cells were maintained at 37 °C in a humidified atmosphere containing 5% CO2. A375, B16F10 melanoma cells, and HSF cells were seeded in 24-well plates (1 × 104 cells/well) and cultured overnight. Transwell chambers with MN of blank, SFMA, DOX, HMnO2/DOX@SFMA groups were placed into wells and incubated under 4 conditions: (1) darkness; (2) 808 nm NIR laser irradiation for 5 min; (3) citric acid buffer treatment; (4) combined 808 nm NIR laser (5 min) + citric acid buffer. Cell proliferation was detected by CCK-8 assay at 24, 48, 72 h; cell viability and death were evaluated by calcein-AM/PI staining.

Antitumor and Antiscarring Effects of HMnO2/DOX@SFMA Microneedles in Animal Models

Male C57BL/6 mice (5–6 weeks old) were subcutaneously injected with 1 × 107 cells/mL B16F10 cells on the right dorsal side. When the initial tumor volume reached approximately 100 mm3, 90% of the tumor mass was surgically resected, leaving a residual tumor burden of approximately 13–15 mm3. Microneedle patches from the blank, HMnO2, DOX, and HMnO2/DOX groups were then applied to the wound site, covered with transparent film, and irradiated with 808 nm NIR (1.50 W/cm2) for 15 min once daily within 3 days postoperation. Wound photographs were acquired at designated time points under standardized conditions (fixed distance, consistent angle, and uniform lighting) to ensure comparability across groups and time points. Tumor size was monitored during the observation period using caliper measurements, and tumor volume was calculated as V = LW 2/2 (L, longest diameter; W, shortest diameter). On day 15, mice were sacrificed and the excised tumors were collected, photographed together with a millimeter ruler under standardized imaging conditions, and used for end point tumor-burden assessment. The projected area of each excised tumor was quantified from the photographs using image-analysis software, and the results were plotted as individual data points with mean ± SD (n = 5) for each group. Tumor and wound tissues were subsequently harvested for histological and molecular analyses.

HE Staining

Deparaffinized tissue sections were immersed in xylene for 5–10 min twice and then rehydrated through a graded ethanol series (100%, 95%, 80%, and 70%; 2–3 min each), followed by rinsing with distilled water. The sections were stained with hematoxylin for 5–10 min, rinsed with distilled water, differentiated in acid alcohol until the nuclei became distinct, rinsed again, and blued in weak alkaline solution (e.g., ammonia water) for 1–2 min. After a final rinse with distilled water, the sections were counterstained with eosin for 1–3 min, dehydrated through graded ethanol solutions (70%, 80%, 95%, and 100%), cleared twice in xylene (5–10 min each), mounted with neutral resin, and observed under a light microscope.

Masson Staining

Paraffin-embedded tissue sections were deparaffinized and rehydrated according to standard procedures. The sections were stained with Weigert’s iron hematoxylin for 5–10 min, rinsed with distilled water, differentiated briefly in acid alcohol, rinsed again, and blued under running water for 5–10 min. Subsequently, the sections were stained with ponceau-fuchsin for 5–10 min and rinsed with distilled water. After differentiation in 1% phosphomolybdic acid for 3–5 min, the sections were directly stained with aniline blue for 5–10 min without intermediate rinsing. The sections were then briefly rinsed with 0.2% acetic acid for 1–2 min, rapidly dehydrated through 95% and 100% ethanol, cleared twice in xylene (5–10 min each), mounted with neutral resin, and examined under a light microscope. In the stained sections, collagen fibers appeared blue, whereas the cytoplasm and nuclei appeared red.

Western Blot

Cells and tumor tissues were homogenized in RIPA Lysis Buffer (Beyotime Institute of Biotechnology, Shanghai, China) to extract protein. After centrifugation at 6500g/min for 20 min, protein quantification was performed using the BCA protein concentration assay kit (Beyotime Institute of Biotechnology, Shanghai, China). Proteins (50 μg) were separated with SDS-PAGE gels and then transferred onto a PVDF membrane. After blocking at room temperature for 1 h, primary antibodies were applied to the membrane overnight at 4 °C. Then, the membrane was incubated with HRP-conjugated goat antirabbit or antimouse IgG antibodies for 1 h at room temperature. To visualize the protein bands, an enhanced chemiluminescence (ECL) detection kit (Tsea Biotech Co., Shanghai, China) was employed. The details of the utilized antibodies are provided in the Supporting Table.

Statistical Analysis

Statistical analyses were conducted using GraphPad Prism 9. Cell experiments were independently repeated three times, with data presented as mean ± SD. Differences between groups were compared by two-way ANOVA and t test; *p < 0.05, **p < 0.01, ***p < 0.001 were considered statistically significant.

Results and Discussion

Characterization of Nanomaterials

In the present study, a multifunctional reactive MN patch coloaded with HMnO2 and DOX, designated as HMnO2/DOX@MN, was developed to address these unmet clinical needs (Figure ). Representative TEM images showed that both HMnO2 and HMnO2/DOX nanoparticles exhibited similar spherical morphology. The particle size distributions shown in Figure B,C were measured by DLS and represent the hydrodynamic diameters of the nanoparticles in aqueous solution. The average hydrodynamic diameters of HMnO2 and HMnO2/DOX were 248.2 ± 7.0 nm and 254.0 ± 1.3 nm, respectively, suggesting that DOX loading did not significantly affect the overall particle size in dispersion. Additionally, Furthermore, the potential of HMnO2 was −32.7 ± 1.11 mV, while that of HMnO2/DOX was −16.1 ± 1.07 mV; the increase in surface potential following drug loading may enhance the phagocytosis of the nanoparticles, thereby promoting their cellular uptake. Ultraviolet–visible (UV–vis) spectroscopic analysis (Figure D) confirmed the successful loading of DOX onto HMnO2, as evidenced by a distinct absorbance peak at 485 nm. Based on the linear regression equation (Y = 0.0189x + 0.0365, R 2 = 0.999), the drug-loading efficiency (DLE) and encapsulation efficiency (EE) were calculated to be 30.9 and 92.9%, respectively.

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Schematic diagram of the preparation of responsive microneedle patch and their application in postoperative treatment of melanoma.

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Synthesis and characterization of HMnO2/DOX. (A) TEM images of HMnO2 (a) and HMnO2/DOX (b); (B, C) particle size distribution profiles of HMnO2 (B) and HMnO2/DOX (C); (D) ultraviolet–visible (UV–vis) spectra of DOX, HMnO2, and HMnO2/DOX; (E–H) photothermal properties of HMnO2: temperature changes (E) and infrared thermal images (G) under different power irradiations at a concentration of 100 μg/mL; temperature changes (F) and infrared thermal images (H) at different concentrations under 1.5 W/cm2 irradiation; (I) temperature variation of HMnO2 during cyclic heating and cooling; (J) drug release profiles of HMnO2/DOX under different pH conditions with or without NIR irradiation; (K) 24-h hemolysis rates of HMnO2 at different concentrations (insets: photographs taken at 24 h); (L) activated partial thromboplastin time (APTT) and prothrombin time (PT) assay results of HMnO2 at different concentrations.

Figure E–H demonstrates that HMnO2 exhibits favorable photothermal properties. Upon irradiation with an 808 nm laser at a power density of 1.5 W/cm2 for 5 min, the temperature of the solution increases to approximately 50 °C at a concentration of 100 μg/mL and exceeds 60 °C at 200 μg/mL (Figure E). Furthermore, HMnO2 displays excellent photothermal stability, maintaining consistent thermal response under repeated irradiation cycles within a short time frame (Figure F), supporting its suitability for multiple therapeutic applications. Therefore, a concentration of 100 μg/mL and a laser power density of 1.5 W/cm2 were selected for subsequent experiments.

As illustrated in Figure G, the cumulative release of DOX from HMnO2/DOX at pH 7.4 is relatively low, reaching only 21.0% over 72 h. However, upon near-infrared (NIR) irradiation, the release rate increases significantly to 58.3%. Under acidic conditions (pH 5.5), approximately 50.1% of DOX is released within the same period, while NIR irradiation further enhances the release to 83.8%. These findings indicate that HMnO2/DOX possesses dual-responsive characteristics, enabling controlled drug release in response to both pH and photothermal stimuli. Moreover, HMnO2 demonstrates good biocompatibility: no hemolysis is observed within 24 h even at a concentration of 200 μg/mL (Figure K). Additionally, coagulation assays show that activated partial thromboplastin time (APTT) and prothrombin time (PT) remain within normal physiological ranges, suggesting minimal interference with the blood coagulation system.

Characterization of Hydrogel Materials

The structure of silk fibroin methacrylate (SFMA) was further characterized via proton nuclear magnetic resonance (1H NMR) spectroscopy, with the results presented in Figure A. Compared to the spectrum of unmodified silk fibroin (SF), new resonance peaks emerged in the SFMA spectrum within the chemical shift ranges of 6.1–6.0 ppm and 5.6–5.5 ppm. These characteristic signals are attributable to the incorporation of glycidyl methacrylate (GMA), thereby confirming the successful functionalization of SF. Additionally, FTIR spectra were used to confirm the successful methacrylation of silk fibroin. As shown in Figure B, both SF and SFMA exhibited the characteristic amide bands of silk fibroin at 1649 cm–1 (amide I), 1514 cm–1 (amide II), and 1231 cm–1 (amide III), indicating that the main protein backbone of silk fibroin was retained after modification. Compared with SF, SFMA showed newly appeared or enhanced absorption peaks in the regions of ∼ 950–1000 cm–1 and 1100–1150 cm–1, which were assigned to the characteristic vibrations of methacrylate groups, including CC–H wagging andCH2-related vibration. These changes demonstrate that methacrylate moieties were successfully introduced into the silk fibroin molecular chain. Therefore, the FTIR results confirmed the successful synthesis of SFMA while preserving the fundamental structural features of silk fibroin. The gelation behavior of SFMA hydrogels at three distinct concentrations was evaluated using the tube inversion test under visible light irradiation (405 nm, 1 min). As illustrated in Figure C, no flow along the tube walls was observed for any of the tested SFMA solutions following Eppendorf tube inversion, demonstrating that the prepared SFMA can rapidly form stable hydrogels upon photoactivation. The rheological properties of the hydrogels were further investigated by monitoring the time-dependent and frequency-dependent evolutions of the storage modulus (G′) and loss modulus (G″), as depicted in Figure D,E. In both cases, G′ consistently exceeded G″ throughout the entire measurement period and across the tested angular frequency range, indicating the formation of a mechanically stable gel network. An ideal hydrogel should possess sufficient mechanical strength to maintain structural integrity during practical applications. As shown in Figure F, the 20% SFMA hydrogel exhibited a maximum compressive stress of 67 kPa, while the 15% SFMA hydrogel reached 45 kPa. These findings suggest that the mechanical properties of the hydrogels can be effectively modulated by adjusting the SFMA concentration, highlighting their potential adaptability for diverse tissue engineering applications. Furthermore, swelling studies (Figure G) revealed that all hydrogels achieved equilibrium swelling within approximately 8 h and maintained a stable swelling ratio thereafter, indicating favorable dimensional stability. The degradation profiles of SFMA hydrogels in phosphate-buffered saline (PBS) are presented in Figure H. The 10% SFMA hydrogel underwent complete degradation by day 28, likely due to its relatively loose network structure, whereas the 15 and 20% SFMA hydrogels remained structurally intact over the 30-day observation period, which is attributed to their denser cross-linked architectures. Moreover, upon contact with tissue exudate, the dextran base layer dissolves, enabling the SFMA tip to remain embedded in the dermis. This design enables localized retention of the drug-loaded tip in the dermis and supports prolonged presence of the delivery system at the target site, although the release of DOX is mainly dictated by the responsive properties of the encapsulated HMnO2/DOX nanoparticles.

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Characterization data of hydrogel microneedles. (A) Proton nuclear magnetic resonance (1H NMR) spectra of SF and SFMA; (B) Fourier transform infrared (FT-IR) spectra of SF and SFMA; (C) gel formation images of water condensates at three concentrations; (D) time-dependent storage modulus (G’) and loss modulus (G’’) curves of different hydrogel materials; (E) frequency-dependent storage modulus (G’) and loss modulus (G’’) curves of different hydrogel materials; (F) stress–strain curves of hydrogels with different component ratios; (G) swelling properties of hydrogels with different component ratios; (H) in vitro degradation behavior of SFMA hydrogels.

Microneedle Data Characterization

SFMA/HMnO2/DOX hydrogel microneedles were successfully fabricated via vacuum-assisted casting of hydrogel precursor solution and nanosuspension into a microneedle mold, followed by degassing, ultraviolet (UV)-induced cross-linking, and demolding (Figure A). The selected mold features a pyramidal tip geometry, which is conducive to efficient skin penetration. Considering that the human stratum corneum ranges from 10 to 40 μm in thickness and the epidermis extends from 40 to 1600 μm, with melanocytes predominantly distributed in the dermal layer, the MNs were engineered with a total height of 800 μm and a base height of 200 μm to enable effective drug delivery to the dermis. As illustrated in Figure B, both the tip and base of blank MNs are transparent; in contrast, the tip of HMnO2/DOX-loaded MNs exhibits a red hue due to the presence of the therapeutic agent, while the base remains transparent as it is composed of soluble glucan. Upon application of the MN patch to biological tissue, contact with tissue exudate triggers dissolution at the tip–substrate interface, leading to detachment of the hydrogel tip, which remains embedded in the tissue. This design enables localized and sustained release of the encapsulated drug, achieving deep-tissue delivery. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) images (Figure C,D) reveal a uniformly arrayed, well-defined pyramidal structure, indicating precise fabrication and dense arrangement on the backing layer. This geometric feature facilitates accurate and rapid insertion into the deeper layers of the skin, enabling noninvasive transdermal delivery to the dermis.

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Characterization of microneedles. (A) Schematic illustration of microneedle (MN) preparation; (B) photographs of MN and HMnO2/DOX@MN; (C) scanning electron microscopy (SEM) image of hydrogel MNs; (D) three-dimensional confocal reconstruction image of hydrogel MNs; (E) single-needle compressive stress curves of hydrogel MNs with different compositions; (F) statistical analysis of single-needle mechanical strength of hydrogel MNs with different compositions; (G) photothermal temperature-rise curves of hydrogel MNs with different compositions; (H) infrared thermal imaging of hydrogel MNs with different compositions; (I) drug release profiles of hydrogels under different conditions; (J) tip morphology of hydrogel MNs; (K) photographs of pigskin after hydrogel MN puncture; (L) confocal z-stack images of subcutaneous drug release simulated by MN puncture in agarose gel.

To ensure effective skin penetration, the microneedle patch must possess an adequate mechanical strength. Therefore, the mechanical properties of microneedle tips with varying compositions were evaluated. Figure E,F presents the stress-displacement curves and corresponding mechanical property data for two groups of microneedles. The results demonstrate that, when compressed to half their tip length (0.4 mm), all prepared microneedles exhibited a fracture force exceeding 0.52 N per needle, surpassing the minimum threshold required for skin penetration. In comparison to blank SFMA microneedles, those loaded with HMnO2/DOX showed a reduced fracture force, which can be likely attributed to structural inhomogeneities or microvoids introduced during drug incorporation within the hydrogel matrix. Notably, prior studies have established that a minimum force of 0.03 N per microneedle is sufficient for effective skin penetration; thus, the fabricated microneedles possess sufficient mechanical robustness to penetrate the skin and enable targeted drug delivery.

The photothermal performance of the SFMA/HMnO2/DOX hydrogel microneedles was further assessed under 808 nm near-infrared irradiation (1.5 W/cm2) (Figure G,H). A significantly enhanced photothermal effect was observed in the HMnO2/DOX microneedles compared to the HMnO2/DOX solution, with infrared thermal imaging revealing no temperature rise in the blank microneedles. In contrast, the HMnO2/DOX microneedles rapidly reached a temperature of 56.8 °C within 5 min of irradiation, demonstrating efficient photothermal conversion. Under combined acidic and photothermal conditions, the cumulative drug release from the hydrogel matrix reached 90.6%, indicating stimuli-responsive release behavior.

Figure I confirms the structural integrity of the microneedle tips postinsertion. As the SFMA hydrogel swells and gradually degrades in the physiological environment, the encapsulated drug is released into the surrounding tissue. Figure K illustrates the microneedle insertion into excised porcine skin, where dissolution at the tip–substrate junction, induced by interaction with tissue fluid, resulted in successful separation of the tips from the backing layer. The resulting array of micropores and residual HMnO2/DOX in the tissue were clearly visible. To further evaluate transdermal delivery depth, agarose gel was used as a skin simulant, and confocal microscopy was employed to visualize drug distribution. As shown in Figure L, confocal z-stack imaging in an agarose gel model showed that the fluorescence signal of loaded DOX could be detected beyond 320 μm from the gel surface after microneedle insertion, indicating effective cargo delivery into the simulated matrix. Considering that microneedle penetration depths reported in the literature are often in the hundred-micrometer range, the observed DOX distribution depth in the agarose model suggests that the SFMA hydrogel microneedles have promising insertion capability.

Inhibitory Effect Evaluation of MN Patch on Melanoma In Vitro

To evaluate the cytocompatibility of HMnO2/DOX@MN, various microneedle formulations were cocultured with human skin fibroblasts (HSFs) under the defined Transwell incubation conditions described in the Materials and Methods section. Live/dead staining showed that most HSFs remained viable in the Ctrl and MN groups, whereas the HMnO2@MN and HMnO2/DOX@MN groups exhibited a small number of dead cells, indicating that drug-loaded formulations induced only slight cytotoxicity under the tested conditions (Figure A). Consistent with these observations, the CCK-8 assay showed that HSF viability was relatively preserved overall, although the HMnO2/DOX@MN group displayed a moderate reduction at later time points compared with the nondrug-loaded groups (Figure B). These findings suggest that HMnO2/DOX@MN retains acceptable cytocompatibility toward fibroblasts, while exerting potent antitumor effects. Subsequently, the in vitro antitumor efficacy of the MN formulations was assessed by coculturing them with B16F10 and A375 cells. Live/dead staining revealed markedly increased tumor cell death in the HMnO2/DOX@MN group compared to the Ctrl, MN, and HMnO2@MN groups (Figure A). Quantitative analysis further confirmed significantly reduced cell viability in both the HMnO2@MN and HMnO2/DOX@MN groups relative to those of the others (Figure B). Overall, these results demonstrate that HMnO2/DOX@MN exhibits strong in vitro antitumor activity while maintaining reasonable biosafety toward HSFs under tested experimental conditions.

5.

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Evaluation of in vitro cytocompatibility and antitumor efficacy of different microneedle formulations. (A) Representative live/dead staining images of HSF, A375, and B16F10 cells after treatment with different formulations (Ctrl, MN, HMnO2@MN, and HMnO2/DOX@MN). Live cells are stained green and dead cells are stained red. Scale bar: 200 μm. (B) CCK-8 assay showing the relative viability of HSF, A375, and B16F10 cells at different time points after treatment with the indicated formulations. Data are presented as mean ± SD. Statistical significance is indicated as *p < 0.05, **p < 0.01, and ***p < 0.001.

Inhibitory Effect Evaluation of MN Patch on Melanoma In Vivo

In the present study, a B16F10 tumor-bearing mouse model mimicking incomplete tumor resection was established to evaluate the in vivo postoperative therapeutic efficacy of the HMnO2/DOX@MN. When the tumor volume reached approximately 100 mm3, a full-thickness circular wound (10 mm in diameter) was created on the dorsal skin of each mouse, followed by surgical removal of 90% of the tumor mass. The wound sites were subsequently treated with patches from the Ctrl, MN, HMnO2@MN, and HMnO2/DOX@MN groups, and the postoperative process was evaluated over a 15-day period. As shown in Figure A, representative photographs of the same mouse in each group at the tumor formation, treatment, and healing stages demonstrated distinct differences in the therapeutic outcome among the groups. The HMnO2/DOX@MN group exhibited the most favorable postoperative course, characterized by progressive wound closure and a minimal visible recurrent tumor burden during the healing stage. In contrast, the Ctrl, MN, and HMnO2@MN groups showed more obvious residual lesions and delayed wound healing. Consistent with these observations, photographs of excised tumors collected at the end point (Figure B) and the corresponding quantification of day 15 end point tumor burden based on the projected area of excised tumors (Figure C) further showed that the HMnO2/DOX@MN group had the lowest residual tumor burden among all groups, whereas the Ctrl and MN groups retained relatively large tumor masses. These findings collectively indicate that HMnO2/DOX@MNs exert the strongest inhibitory effect on postoperative melanoma recurrence while simultaneously promoting wound healing in vivo.

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Intratumoral therapeutic effects of different treatment regimens in the postoperative melanoma model. (A) Representative photographs of the same mouse from each group at three different experimental stages, namely tumor formation, treatment, and wound healing. (B) Photographs of excised tumors from each experimental group. (C) Quantification of day-15 end point tumor burden based on the projected area of excised tumors from each group. Individual data points represent one mouse; bars indicate mean ± SD (n = 5). (D) Representative immunofluorescence staining images of Ki67, CD86, CD206, and HIF-1α in tumor/wound tissue sections from each group. (E) Representative Masson’s trichrome staining images of wound tissues from each group. (F) Representative H&E-stained sections of major organs (lung, liver, kidney, and spleen) from each group for biosafety evaluation.

On day 15, wound tissues were harvested for histopathological and molecular analyses, including hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, and Western blotting (Figures E,F, and S3). Compared with the other treatment groups, the HMnO2/DOX@MN group showed a more intact and organized tissue architecture, together with more advanced features of tissue regeneration. Masson’s staining further revealed improved collagen deposition and tissue remodeling in this group. Consistent with these histological findings, Western blot analysis demonstrated upregulated expression of Collagen Type I and Collagen Type III, indicating enhanced extracellular matrix reconstruction and functional collagen synthesis in the regenerated tissue. Notably, no obvious residual tumor nodules were observed in the newly formed tissue of the HMnO2/DOX@MN group, suggesting effective inhibition of postoperative tumor recurrence.

To further clarify the mechanisms underlying the antitumor and wound-healing effects of HMnO2/DOX@MN, immunofluorescence staining was performed on wound tissues collected 15 days after treatment. In vivo assessments of proliferative activity, immune regulation, and tissue hypoxia were conducted using Ki67, CD86, CD206, and HIF-1α staining, respectively. As shown in Figure D, the HMnO2/DOX@MN group exhibited markedly reduced Ki67 expression compared with the Ctrl, MN, and HMnO2@MN groups, indicating effective suppression of residual tumor-cell proliferation.

Accumulating evidence suggests that modulation of the local immune microenvironment is essential for efficient wound healing. , In particular, macrophages typically undergo a transition from the pro-inflammatory M1 phenotype to the anti-inflammatory and reparative M2 phenotype during the proliferative phase of tissue repair. Consistent with this pattern, the HMnO2/DOX@MN group showed substantially decreased CD86 expression together with increased CD206 expression relative to the other treatment groups, indicating promotion of macrophage polarization toward a reparative phenotype. Since pro-inflammatory cytokines secreted by M1 macrophages, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), can aggravate chronic inflammation, promote tumor progression, and impair wound healing, whereas anti-inflammatory mediators produced by M2 macrophages, including interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), facilitate inflammation resolution, angiogenesis, and tissue remodeling, these findings suggest that HMnO2/DOX@MN contributes to postoperative tissue repair, at least in part, by reshaping the inflammatory microenvironment. , Beyond its immunomodulatory effects, the hypoxia-relieving capability of HMnO2/DOX@MN was supported by both the in vitro oxygen generation assay and the in vivo HIF-1α results (Figures D and S3). Specifically, upon the addition of H2O2, HMnO2/DOX@MN generated oxygen efficiently and showed a clear time-dependent increase in dissolved oxygen concentration, particularly under acidic conditions, consistent with the pH-responsive catalytic behavior of HMnO2 within the tumor microenvironment. In agreement with this observation, HIF-1α staining in vivo was markedly reduced in the HMnO2/DOX@MN group compared with the Ctrl, MN, and HMnO2@MN groups, indicating effective alleviation of tissue hypoxia, as hypoxia is well-known to induce HIF-1α upregulation. , Given that hypoxia promotes tumor progression through HIF-1α-mediated upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), while simultaneously impairing wound repair by suppressing keratinocyte migration, fibroblast proliferation, and collagen synthesis, improvement of local oxygenation may further contribute to both tumor suppression and tissue regeneration. , To further validate these histological observations, flow cytometric analysis was performed on tissues collected from the Ctrl, MN, HMnO2@MN, and HMnO2/DOX@MN groups (Figure S1). The proportion of CD86-positive cells progressively declined from 31.7% in the Ctrl group to 23.3% in the MN group, 18.8% in the HMnO2@MN group, and 5.95% in the HMnO2/DOX@MN group, indicating effective suppression of the pro-inflammatory phenotype. In contrast, the proportion of CD206-positive cells increased from 2.11% in the Ctrl group to 9.14% in the MN group, 10.6% in the HMnO2@MN group, and 25.0% in the HMnO2/DOX@MN group, further supporting macrophage polarization toward a pro-repair phenotype. In parallel, the proportion of Ki67-positive cells decreased from 9.95% in the Ctrl group to 5.75% in the MN group, 4.91% in the HMnO2@MN group, and 1.58% in the HMnO2/DOX@MN group, consistent with reduced proliferative activity of residual tumor cells. Similarly, HIF-1α-positive cells declined from 24.8% in the Ctrl group to 20.5% in the MN group, 18.3% in the HMnO2@MN group, and 8.29% in the HMnO2/DOX@MN group, further confirming mitigation of the hypoxic microenvironment. Together, these flow cytometry data were in good agreement with the immunofluorescence findings and provided additional quantitative evidence that HMnO2/DOX@MN suppresses inflammation-associated tumor progression, promotes macrophage polarization toward an M2-like reparative phenotype, reduces tumor-cell proliferation, and alleviates tissue hypoxia. Collectively, these findings indicate that the therapeutic benefit of HMnO2/DOX@MN is not limited to direct tumor ablation, but also involves coordinated remodeling of the postoperative tumor microenvironment through attenuation of pro-inflammatory signaling, enhancement of reparative immune responses, reduction of proliferative activity, and improvement of local oxygenation.

Conclusions

In summary, our study successfully developed a straightforward responsive HMnO2/DOX@MN patch for integrated postoperative melanoma therapy and wound healing. This multifunctional platform incorporates the dual-responsive drug release of HMnO2/DOX, the superior mechanical and biodegradable properties of the SFMA hydrogel, and the enhanced therapeutic effect of PTT and chemotherapy. The in vitro and in vivo results both demonstrate that HMnO2/DOX@MN effectively suppresses postoperative tumor recurrence, modulates the inflammatory microenvironment, alleviates tissue hypoxia, and promotes accelerated wound closure. With further optimization and preclinical validation, this microneedle system shows significant potential as a novel adjuvant therapy for postoperative melanoma management, addressing key clinical challenges such as residual tumor elimination and enhanced wound repair.

This study is subject to several limitations. First, in vivo experiments were performed using a murine melanoma model, necessitating further investigations in larger animal models that are required to assess translational potential, particularly in light of species-specific differences in hypoxia response and macrophage function. Second, the long-term biocompatibility and biodegradation behavior of the SFMA hydrogel require a more comprehensive assessment to rule out potential chronic inflammatory responses or accumulation of degradation byproducts. Third, although the present therapeutic strategy integrates PTT and chemotherapy, the current study did not include a DOX@MN monotherapy group; therefore, the relative contribution of chemotherapy alone versus the combined treatment could not be rigorously distinguished, and the therapeutic advantage of HMnO2/DOX@MN should be interpreted as an enhanced combined effect rather than a strictly demonstrated synergistic effect. In addition, incorporation of immunomodulatory agents or immune checkpoint inhibitors may further improve antimetastatic efficacy by promoting systemic antitumor immunity. Furthermore, future studies should explore the interplay among hypoxia alleviation, macrophage polarization, and other stromal cell populations, such as fibroblasts and endothelial cells, to more fully elucidate the multifaceted mechanisms underlying the therapeutic effects of HMnO2/DOX@MN.

Supplementary Material

am6c02463_si_001.pdf (343.1KB, pdf)

All data generated or analyzed during this study are included in this published article and its Supporting Information files.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.6c02463.

  • The antibodies involved in the article (Table S1); representative flow cytometry plots of CD86, CD206, Ki67, and HIF-1α in different treatment groups (Figure S1); Western blot analysis of collagen type I and type III expression in wound tissue (Figure S2); in vitro oxygen generation behavior of HMnO2/DOX@MN after H2O2 addition (Figure S3) (PDF)

X. Zhang conceived the idea. X. Zhang carried out the study and drafted the manuscript. Y.Z., L.M., X. Zhou, J.H., D.K., S.L., and M.C. conducted the experiments. This article was completed under the guidance of R.Y. All authors participated in the discussion of the results and wrote the manuscript.

This study was supported by National Natural Science Foundation of China (82272276).

All animal handling procedures were approved by the Animal Care and Use Committee of Guangzhou First People’s Hospital.

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

am6c02463_si_001.pdf (343.1KB, pdf)

Data Availability Statement

All data generated or analyzed during this study are included in this published article and its Supporting Information files.

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