Injectable Thermoresponsive Hybrid Hydrogel for Localized Chemo-Immunotherapy via Co-Delivery of Doxorubicin-Loaded Tumor-Derived Exosomes and Immunoadjuvants

The therapeutic efficacy of melanoma immunochemotherapy is severely limited by insufficient intratumoral drug retention, systemic toxicity, and immunosuppressive tumor microenvironment (TME). Thus, we developed a single-dose injectable localized chemo-immunotherapy platform that enables sustained tumor-restricted delivery and synergistic immune remodeling. This hybrid system integrates doxorubicin-loaded tumor-derived exosome-coated hollow mesoporous silica nanoparticles (DeH) with a mannose-modified β-cyclodextrin-polyethyleneimine carrier co-delivering dual Toll-like receptor agonists (RC-MCP) within a thermoresponsive polypeptide hydrogel (mPEG- b -PELG). The biomimetic exosome coating provides an exosome-sheathed nanostructure and amplifies doxorubicin-induced immunogenic cell death. Mannose-mediated targeting facilitates preferential uptake by antigen-presenting cells and enhances endosomal Toll-like receptor signaling, leading to robust dendritic cell maturation. Following intratumoral injection, the hydrogel undergoes in situ sol-gel transition to form a stable drug depot, enabling sustained and coordinated release while minimizing systemic exposure. As a result, a single intratumoral administration elicits potent antitumor immune responses, significantly suppresses tumor growth, alleviates TME immunosuppression, and exhibits favorable biocompatibility in murine melanoma model. Collectively, this work presents a rationally designed single-dose localized chemo-immunotherapy strategy for melanoma treatment.