Chiral Nanofibers of Camptothecin Trigger Pyroptosis for Enhanced Immunotherapy

Camptothecin (CPT), a chemotherapeutic agent, demonstrates significant potential in cancer therapy. However, as a drug, CPT molecule suffers from poor water solubility, limited bioavailability, and insufficient immune response. Herein, we construct CPT nanofibers (CNF) with a right-handed chiral property via supramolecular self-assembly, which significantly overcomes the solubility barriers associated with bioavailability and improves tumor immune prognosis. The CNF exhibits high chiral asymmetry factor (gabs) (~ 0.11) and remarkable structure stability under pH 6.5 condition. By formulating chiral CNF with mitochondrial-targeted DSPE-PEG-TPP, CNF accumulates specifically in the mitochondria of cancer cells, leading to mitochondrial dysfunction and a 3.42-fold increase in reactive oxygen species (ROS) generation compared to the CPT molecule. This ROS amplification activates the caspase-1/gasdermin D (GSDMD) pathway, inducing pyroptosis that promotes M1 macrophage polarization and enhences CD8+ T-cell-dependent antitumor immunity. Consequently, CNF achieves 1.8-fold greater growth inhibition of distant tumor and reduces tumor metastasis compared to the CPT molecule. Our innovative platform, assembling CPT molecules into chiral CNF structure, is highly anticipated to overcome the current clinical limitations of CPT molecules and offer a new direction for the development of next-generation immunotherapy strategies.