Ganoderma lucidum polysaccharide-decorated extracellular vesicle enables synergistical antitumor immunotherapy

<i>Ganoderma lucidum</i> 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.