Translating Supramolecular Design Principles to Camptothecin for Precision and Targeted Cancer Therapy

ConspectusCancer, responsible for approximately 16.8% of global mortality, remains one of the most formidable challenges to public health. Chemotherapy remains a mainstay of cancer treatment, utilizing small-molecule agents to inhibit tumor growth, invasion, and metastasis. Camptothecin (CPT) exhibits broad-spectrum antitumor activity; however, its clinical potential is severely limited by poor aqueous solubility, low stability, and insufficient tumor selectivity, which collectively restrict its bioavailability and therapeutic efficacy. Conventional formulations such as covalent chemical modifications, lipid encapsulations and PEGylated conjugates have been developed to address these issues but often suffer from short half-lives, low drug-loading capacities (<20%), instability under physiological conditions, and inadequate tumor accumulation.Inspired by natural self-assembly processes exemplified by DNA and collagen, supramolecular chemistry offers a versatile approach to constructing dynamic, programmable architectures through noncovalent interactions. These systems mimic biological organization and enable tunable functionalities for drug delivery, tissue regeneration, and immune modulation. Over the past decade, our group has established an approach that precisely controls supramolecular self-assembly and chiral nanostructure formation through the elucidation of how specific noncovalent interactions govern assembly dynamics, thereby transforming supramolecular chemistry into a programmable platform for diverse biomedical applications such as biocatalysis, regenerative medicine, and cancer therapy. All the results have demonstrated the superiority of supramolecular chiral nanofiber structures in biofields. Expanding on this groundwork, we have successfully transformed CPT from a conventional small-molecule chemotherapeutic into a supramolecular chiral nanofibers’ therapeutic platform. Through a straightforward self-assembly strategy driven by noncovalent interactions, CPT molecules can spontaneously self-assemble into controllable helical nanofibers without the need for additional chemical modification. The obtained dynamic self-assemblies exhibit improved stability, high drug loading, and efficient tumor penetration by targeting the mitochondria, achieving precise subcellular localization and robust induction of immunogenic cell death, thus representing a minimalist yet powerful approach to supramolecular cancer therapy.This Account highlights our group’s recent advances in chiral supramolecular materials for cancer therapy, which have pioneered a supramolecular engineering approach for CPT-based treatment. We first discuss the design of responsive nanostructures that exploit physical stimuli within the tumor microenvironment (TME) for controlled drug release. Subsequently, we delve into the novel strategy of chirality-driven tumor immunotherapy. A specific focus is placed on potent chiral supramolecular assemblies, particularly CPT-based nanofibers, which exemplify this immunotherapeutic approach. Following the discussion of these scientific breakthroughs, we address the critical challenges in translating such supramolecular materials from the laboratory to clinical trials. It is hoped that the insights provided here will serve as a valuable foundation for integrating supramolecular engineering with translational oncology, thereby paving the way toward precision supramolecular therapeutics.