Oxygen-Generating Transdermal Nanoplatform Codelivering BRD4 Proteolysis-Targeting Chimera/Verteporfin/CaO2 Synergistically Remodels Immunosuppressive Melanoma Microenvironment to Potentiate Combination Immunotherapy

Melanoma relapse and metastasis remain formidable clinical challenges, with the inadequate immunogenicity and highly immunosuppressive tumor microenvironment (ITME) presenting serious obstacles to current postsurgical immunotherapies. Herein, an oxygen self-supplying core-shell microneedle patch (AV@LDL&CaO2 MNs) featuring multiple innovative anticancer therapies and multimodal immunomodulatory properties is developed to facilitate melanoma postoperative management. Specifically, recombinant low-density lipoprotein nanoparticles (AV@LDL NPs) embedding both the bromodomain containing protein 4 (BRD4)-targeting proteolysis-targeting chimera (PROTAC) ARV825 and the photosensitizer verteporfin are strategically incorporated into the dissolvable shell, while the oxygen-generating nanoreactor (HA@CaO2 NPs) occupies the core compartment. Upon insertion, the MN needles dissolve immediately, and the exposed HA@CaO2 NPs subsequently decompose within the acidic tumor microenvironment, yielding O2 and Ca2+, which augment verteporfin-based photodynamic therapy (PDT) efficacy and exacerbate mitochondrial damage via reactive oxygen species (ROS) storms, collaboratively boosting immunogenicity via dual immunogenic cell death (ICD) induction. Concurrently, ARV825 downregulates the intratumoral infiltration of M2-type tumor-associated macrophages (TAMs), and along with hypoxia all eviation, effectively remodels the ITME. Moreover, ARV825 acts like a PD-L1 blocking agent, cooperatively inhibiting immune evasion and resistance. Notably, AV@LDL&CaO2 MNs achieved a 90.0% melanoma inhibition rate, and elicited robust systemic immune protection against recurrence and metastasis with low-dose administration and minimal toxicity, offering a self-managing and innovative photodynamic-epigenetic-metallo-immunotherapy strategy for efficient postoperative melanoma management.