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Updated: Jul 24, 2025
Author Spotlight: Innovative Microneedle-Based Strategies for Enhanced Exosome Delivery and Stability
Published on: July 12, 2024
Dissolving microneedles-based programmed delivery system for enhanced chemo-immunotherapy of melanoma
Yu Tian1, Hongshu Jing1, Quan Wang2
1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Immune checkpoint blockade, especially the programmed cell death ligand 1 (PD-L1) blockade, has revolutionized the treatment of melanoma. However, PD-1/PD-L1 monotherapy leads to unsatisfactory therapeutic outcomes. The immunotherapy of melanoma could be improved by adding doxorubicin (DOX), which triggers immunogenic cell death (ICD) effect to activate anti-tumor immunity. Additionally, microneedles, especially dissolving microneedles (dMNs), can further enhance outcomes of chemo-immunotherapy due to the physical adjuvant effect of dMNs. Herein, we developed the dMNs-based programmed delivery system that incorporated pH-sensitive and melanoma-targeting liposomes to co-deliver DOX and siPD-L1, achieving enhanced chemo-immunotherapy of melanoma (si/DOX@LRGD dMNs). The incorporated si/DOX@LRGD LPs demonstrated uniform particle size, pH-sensitive drug release, high in vitro cytotoxicity and targeting ability. Besides, si/DOX@LRGD LPs effectively downregulated the expression of PD-L1, induced tumor cell apoptosis and triggered ICD effect. The si/DOX@LRGD LPs also showed deep penetration (approximately 80 μm) in 3D tumor spheroids. Moreover, si/DOX@LRGD dMNs dissolved rapidly into the skin and had sufficient mechanical strength to penetrate skin, reaching a depth of approximately 260 μm in mice skin. In mice model of melanoma tumor, si/DOX@LRGD dMNs exhibited better anti-tumor efficacy than monotherapy by dMNs and tail intravenous injection at the same dose. This was due to the higher cytotoxic CD8+ T cells and the secreted cytotoxic cytokine IFN-γ evoked by si/DOX@LRGD dMNs, thereby eliciting strong T-cell mediated immune response and resulted in enhanced anti-tumor effects. In conclusion, these findings suggested that si/DOX@LRGD dMNs provided a promising and effective strategy for enhanced chemo-immunotherapy of melanoma.
Insights
This study developed dissolving microneedles (dMNs) for melanoma treatment, combining doxorubicin (DOX) and programmed cell death ligand 1 (PD-L1) blockade. The dMNs enhanced chemo-immunotherapy by activating anti-tumor immunity and improving drug delivery for better outcomes.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Immune checkpoint blockade, particularly PD-L1 blockade, has advanced melanoma treatment.
- PD-1/PD-L1 monotherapy shows limited efficacy in melanoma.
- Doxorubicin (DOX) can enhance immunotherapy by inducing immunogenic cell death (ICD).
- Dissolving microneedles (dMNs) offer physical adjuvant effects to improve chemo-immunotherapy.
Purpose of the Study:
- To develop a dMN-based delivery system for co-delivering DOX and siPD-L1 for enhanced melanoma chemo-immunotherapy.
- To create pH-sensitive, melanoma-targeting liposomes (LPs) for efficient drug delivery.
- To evaluate the therapeutic efficacy of the novel si/DOX@LRGD dMNs system.
Main Methods:
- Formulation of pH-sensitive, melanoma-targeting liposomes (LPs) co-delivering DOX and siPD-L1 (si/DOX@LRGD LPs).
- Fabrication of dMNs loaded with si/DOX@LRGD LPs.
- In vitro characterization of LPs (particle size, drug release, cytotoxicity, targeting).
- In vitro assessment of si/DOX@LRGD LPs for PD-L1 downregulation, apoptosis induction, and ICD.
- Evaluation of dMNs penetration depth in 3D tumor spheroids and mouse skin.
- In vivo anti-tumor efficacy study in a mouse melanoma model comparing si/DOX@LRGD dMNs with monotherapy and intravenous injection.
Main Results:
- si/DOX@LRGD LPs exhibited uniform size, pH-sensitive release, high in vitro cytotoxicity, and targeting ability.
- si/DOX@LRGD LPs effectively reduced PD-L1 expression, induced tumor cell apoptosis, and triggered ICD.
- si/DOX@LRGD LPs demonstrated deep penetration in 3D tumor spheroids (~80 μm).
- si/DOX@LRGD dMNs rapidly dissolved and penetrated mouse skin (~260 μm).
- si/DOX@LRGD dMNs showed superior anti-tumor efficacy compared to monotherapy and intravenous administration.
- Enhanced anti-tumor effects were attributed to increased cytotoxic CD8+ T cells and IFN-γ secretion.
Conclusions:
- si/DOX@LRGD dMNs represent a promising strategy for enhanced melanoma chemo-immunotherapy.
- The dMN-based delivery system effectively co-delivers DOX and siPD-L1, improving therapeutic outcomes.
- This approach leverages ICD and targeted delivery for potent anti-tumor immune responses.
