Sporoderm-Removed Particles Enhance Oxaliplatin Immunochemotherapy against Colorectal Cancer and Mitigate Neurotoxicity via Dual-Directional PINK1/Parkin Mitophagy

Abstract

Oxaliplatin (OXA) is a widely used and effective first-line chemotherapeutic agent for colorectal cancer. However, its therapeutic benefits are often constrained by limited antitumor immune activation and dose-limiting peripheral neurotoxicity. Here, we report that sporoderm-removed particles from Ganoderma lucidum spores (RGLS), a naturally derived bioactive particulate system, orchestrate bidirectional regulation of PINK1/Parkin-mediated mitophagy to simultaneously enhance OXA efficacy and mitigate neurotoxicity. Sporoderm removal remodeled the particle biointerface, improved the hydrophilicity of RGLS, and facilitated the release of bioactive constituents in gastrointestinal fluids, thereby increasing their bioavailability. In tumor tissues, RGLS cooperated with OXA to intensify mitochondrial dysfunction and excessive mitophagy, leading to increased tumor cell death and amplified immunogenic cell death, as indicated by enhanced calreticulin exposure and HMGB1 release. This immunogenic remodeling promoted dendritic cell maturation, increased intratumoral infiltration of CD4+ and CD8+ T cells, and attenuated OXA-induced PD-L1 upregulation, collectively converting immune-cold tumors into immune-hot phenotypes. In contrast, in dorsal root ganglia, RGLS restored OXA-impaired PINK1/Parkin-dependent mitochondrial quality control, reduced mitochondrial reactive oxygen species accumulation, and protected neurons from chemotherapy-induced injury, thereby alleviating peripheral neuropathy. These findings establish sporoderm removal as a biointerface-modulation strategy for transforming Ganoderma lucidum spores into multifunctional therapeutic particles and highlight RGLS as a promising adjuvant platform to improve the therapeutic index of OXA-based colorectal cancer chemotherapy.