Tea leaf-derived nanovesicles for ferric-supply-amplified ICD and macrophage reprogramming to boost immunotherapy against head and neck squamous carcinoma

Combination of multiple immune activation pathways that can modulate different immune axes in coordination has been found extremely effective in amplifying immunotherapy. In this study, by using the naturally occurring tea leaf-derived nanovesicles (TDNVs), we prepare an all-in-one multifunctional immunotherapeutic nanomedicine (denoted as DFeTNVs) by co-loading chemotherapeutic drug, doxorubicin (DOX), into a ferric-engineered TDNVs. Owing to the acid-triggered responsiveness, the loaded cargoes (DOX and Fe 3+ ) would be released in the tumor acidic microenvironment to elicit DOX-mediated immunogenic cell death (ICD), which is further enhanced by the ferric ions-mediated Fenton reaction. Strikingly, the inherent surface galactose of DFeTNVs could promote specific cellular uptake of macrophages through galactose-type lectin-mediated endocytosis so as to deliver Fe 3+ inside macrophages for potentiating the polarization of M2-like tumor-associated macrophages (TAMs) into M1 phenotype, thereby boosting the macrophage-mediated phagocytosis and T cell activation. All these contribute to evoking a strong anticancer immune response, especially in combination with anti-PD-L1 antibody, to inhibit tumor growth. The present work provides a delicate design integrated with multiple functions (i.e., drug loading, metal chelation, intrinsic targeting) without using excessive chemical ligands or complex synthetic processes, promising the feasibility of this immunotherapeutic nanosystem for future clinical applications.