Nanovesicles With Mechanically Induced Adjuvanticity for Robust Melanoma Vaccination Toward Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) are abundant in tumor microenvironment (TME) but fail to act as vaccine targets due to their inferior immune response. Here, a robust strategy was presented to develop potent cancer vaccines toward TAMs via a multi-functional adjuvant, breaking through the conventional vaccine design centered on dendritic cells (DCs). To address this issue, rigidity-tunable nanovesicles (P-Pm) were engineered by surface decoration of Chol-PItEGm with precise regulation of chain lengths. The P-Pm nanovesicle exerted mechanically induced adjuvanticity through not only enhancing endocytosis in a rigidity-dependent manner to facilitate antigen delivery and processing in TAMs, but also activating the mechanosensitive Piezo1/YAP/TAZ signaling pathway to promote M2-like TAMs reprogramming. Furthermore, the rigid P-Pm nanovesicle could efficiently co-encapsulate antigenic gp100 peptide and toll-like receptor agonist resiquimod (R848) to form an anti-melanoma vaccine P@Rg-Pm. After intravenously injected, CD8+ T cell infiltration was increased while immune-suppressive cell level of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) were decreased along with elevated levels of proinflammatory factors including IL-1β, IFN-γ, and IL-12, demonstrating the effective reversal of immunosuppressive TME. Consequently, P@Rg-Pm demonstrates significant antitumor efficacy against B16-F10 melanoma in both therapeutic and prophylactic models without any assistance of other therapies.