Chiral Covalent Organic Frameworks Trigger Tumor-Specific Mitophagy via Notch/Mitogen-Activated Protein Kinase Pathways and Enantiomer-Dependent Photodynamic Therapy

Chirality enlightens promising antitumor strategies. However, the limited understanding of chirality-associated cellular metabolism regulation and cell death mechanisms impede the rational design of chirality-dependent functional nanoplatforms for safe and effective antitumor therapy. In this work, we engineered a propargylamine-linked chiral covalent organic framework (CCOF) and conducted a comprehensive examination of its interactions with living organisms and its cytotoxicity. Our findings demonstrate that CCOF enters tumor cells in a chirality-dependent manner, induces mitochondrial autophagy, and thereby promotes cell death. Furthermore, the efficiency of autophagy activation is influenced by chirality, with (S)-DTzP-COF being more potent than (R)-DTzP-COF. Subsequent high-throughput transcriptomics analysis unveiled the mechanisms underlying CCOF’s efficacy against tumors. Additionally, CCOF demonstrates enantiomer-dependent performance in the photocatalytic oxidation of oxygen under laser irradiation, both in vitro and in vivo. Under laser irradiation, the proposed CCOF nanoplatform achieves the desired antitumor effect in three different subcutaneous tumor models. This study represents an application of CCOFs in oncology, uncovering a chirality-dependent mechanism of mitochondrial autophagy induction, with (S)-DTzP-COF engaging the Notch signaling pathway in addition to both (R)-DTzP-COF and (S)-DTzP-COF being involved in the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. These discoveries lay a robust foundation for the advancement of chiral nanomaterials in biomedical application.