Ganoderma lucidum polysaccharide-decorated extracellular vesicle enables synergistical antitumor immunotherapy

Ganoderma lucidum polysaccharide (GLP) holds considerable promise for tumor therapy, but its clinical application is limited by its poor tumor-targeting capability. Herein, we report the development of an immunoregulatory nano-bioconjugate formed by conjugating GLPs with low-pH culture medium reprogrammed CT26 tumor cell-derived extracellular vesicle (LTEV). Specifically, 4-carboxybenzeneboronic acid (CPBA), used as an intermediate coupling agent, is conjugated with the amino group of LTEV via its carboxyl group to obtain CPBA-LTEV. GLP is then covalently linked via boric ester linkages between its hydroxyl groups and the boronic acid groups of CPBA. After systemic administration, GLP@LTEV accumulates in homologous tumor tissues derived from the LTEV parent cells, remodeling the immunosuppressive tumor microenvironment (TME) by repolarizing M2-like macrophages towards the M1 phenotype, promoting dendritic cell (DC) maturation, activating cytotoxic T lymphocytes (CTLs), and inhibiting immunosuppressive regulatory T cells (Tregs). The synergism of tumor-targeting delivery and potent immunomodulatory effects in this combined manner therefore significantly inhibits subcutaneous tumor growth and lung metastasis with minimal side effects, providing a novel combination of polysaccharide and nanovesicle for robust tumor immunotherapy. GLP@LTEV effectively accumulates in tumor tissues and significantly reverse the immunosuppressive TME via repolarizing M2 macrophages towards M1 phenotype, promoting DC maturation, activating CTLs, and inhibiting Tregs for robust tumor immunotherapy.