Multicomponent Ganoderma lucidum spore-based solid self-nanoemulsifying system of paclitaxel for improved lymphatic absorption and immune synergistic antitumor strategy

Abstract

In colorectal cancer, the cancer-immunity cycle is often disrupted by the lack of effective tumor-associated antigens, impaired activation of antigen-presenting cells, and insufficient T cell infiltration, leading to tumor immune escape and disease progression. Therefore, we developed PTX-GLSO SEDDS@GLS (PGS@GLS), a multicomponent solid self-emulsifying drug delivery system (SEDDS) incorporating paclitaxel (PTX) and Ganoderma lucidum spore oil (GLSO), with processed Ganoderma lucidum spores (GLS) as the solid carrier. The intestinal lymphatic absorption of PTX-GLSO SEDDS was significantly enhanced after GLS solidification, facilitating the induction of immune responses. Additionally, the oil phase of GLSO enhanced PTX solubility through self-emulsification into nanoemulsion. In tumors and the mesenteric lymphatic system, PGS@GLS induced robust immunogenic cell death and triggered the release of damage-associated molecular patterns, thereby initiating the cancer-immunity cycle. Furthermore, GLSO and GLS synergistically promoted dendritic cell maturation and cytotoxic T cell activation, thereby potentiating anti-tumor immune responses. Tumor cells were killed by the accumulated cytotoxic T cells, and the resulting dead tumor cells released additional tumor-associated antigens, which were subsequently presented by dendritic cells, creating a positive feedback loop to amplify the cancer-immunity cycle. Notably, PGS@GLS maintained potent antitumor efficacy while mitigated PTX-related systemic toxicity, representing a promising oral chemoimmunotherapy platform that restores antitumor immunity through lymphatic transport-mediated cancer-immunity cycle reinforcement.