Background

Camptothecin (CPT), an important chemotherapeutic drug, is widely used in cancer treatment due to its potent inhibition of topoisomerase I. However, CPT faces several challenges in clinical applications, including poor water solubility, low bioavailability, and insufficient immune responses. These limitations hinder its therapeutic efficacy in cancer treatment and make it difficult to effectively activate anti-tumor immune responses. To overcome these constraints, researchers have attempted strategies such as covalent conjugation, host-guest inclusion, and carrier-assisted delivery to improve CPT's performance. However, these methods often involve complex synthesis, high costs, and inadequate immunogenicity. Therefore, developing a simple, efficient CPT delivery system capable of enhancing immune responses is of great importance.

Content

Recently, the team led by Feng Chuanliang from the School of Materials Science and Engineering at Shanghai Jiao Tong University published a paper titled "Chiral Nanofibers of Camptothecin Trigger Pyroptosis for Enhanced Immunotherapy" in Angewandte Chemie International Edition. They constructed right-handed CPT nanofibers (CNF) via supramolecular self-assembly, which significantly overcame solubility barriers related to bioavailability and improved tumor immune prognosis. The CNF exhibited a high chiral asymmetry factor (gabs) of approximately 0.11 and excellent structural stability under pH 6.5 conditions. By formulating chiral CNF with the mitochondria-targeting DSPE-PEG-TPP, CNF specifically accumulated in the mitochondria of cancer cells, leading to mitochondrial dysfunction and a 3.42-fold increase in reactive oxygen species (ROS) production compared to CPT molecules. This ROS increase activated the caspase-1/gasdermin D (GSDMD) pathway, inducing pyroptosis, promoting M1-type macrophage polarization, and enhancing CD8⁺ T cell-dependent anti-tumor immunity. Consequently, CNF showed a 1.8-fold greater inhibition of distant tumor growth and reduced tumor metastasis compared to CPT molecules. This innovative platform of assembling CPT molecules into chiral CNF structures holds promise for overcoming the current clinical limitations of CPT and providing new directions for the development of next-generation immunotherapy strategies.

Highlights

1. Construction and Properties of Chiral Nanofibers

• Researchers successfully constructed right-handed camptothecin nanofibers (CNF) via supramolecular self-assembly, demonstrating high optical activity and excellent structural stability (stable for 75 hours under pH 6.5 conditions).
• CNF exhibited uniform diameter (~198 ± 58 nm) with good monodispersity and reproducibility.

2. Mitochondria-Targeted ROS Generation and Pyroptosis

• CNF, modified with DSPE-PEG-TPP, achieved targeted delivery to tumor cell mitochondria, significantly increasing ROS production (3.42-fold higher than CPT molecules).
• This ROS increase activated the caspase-1/GSDMD pathway, inducing pyroptosis, thereby promoting M1-type macrophage polarization and enhancing CD8⁺ T cell-dependent anti-tumor immune responses.

3. Significant Anti-Tumor Effects

• In vitro experiments showed CNF had a 1.25-fold lower half-maximal inhibitory concentration (IC₅₀) than CPT, indicating stronger cytotoxicity.
• In vivo experiments demonstrated that CNF-treated mice exhibited an 80.4% tumor inhibition rate, 1.4-fold higher than the CPT-treated group. Furthermore, CNF significantly inhibited the growth of distant tumors (66.3% inhibition rate), 1.8-fold higher than CPT, showcasing potent systemic immunotherapeutic effects.

4. Remodeling of the Immune Microenvironment

• CNF activated immune responses and remodeled the immunosuppressive tumor microenvironment by inducing pyroptosis and the release of damage-associated molecular patterns (DAMPs).
• In tumor-draining lymph nodes, CNF significantly increased the proportion of mature dendritic cells (DCs) and enhanced the infiltration of CD8⁺ cytotoxic T cells in tumor tissues while reducing the proportion of immunosuppressive Tregs.
• CNF also promoted the polarization of tumor-associated macrophages (TAMs) from the M2 to the M1 phenotype, further enhancing anti-tumor immune responses.

5. Innovation and Application Prospects

• This study provides a novel CPT delivery platform based on supramolecular self-assembly, significantly improving CPT's water solubility, bioavailability, and immunogenicity through the construction of chiral nanofiber structures.
• This strategy not only overcomes the limitations of traditional CPT drugs but also offers new directions for the development of next-generation immunotherapy strategies, promising a more efficient and safer solution for clinical cancer treatment.

Reference

F. Gao, X. Qiu, S. Baddi, et al., Chiral Nanofibers of Camptothecin Trigger Pyroptosis for Enhanced Immunotherapy, Angew. Chem. Int. Ed., 2025, 64, e202423446.

Link

https://doi.org/10.1002/anie.202423446