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

ABSTRACT 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‐P m ) were engineered by surface decoration of Chol‐PItEG m with precise regulation of chain lengths. The P‐P m 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‐P m nanovesicle could efficiently co‐encapsulate antigenic gp100 peptide and toll‐like receptor agonist resiquimod (R848) to form an anti‐melanoma vaccine P@Rg‐P m . 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‐P m demonstrates significant antitumor efficacy against B16‐F10 melanoma in both therapeutic and prophylactic models without any assistance of other therapies.