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.