The Ballet of Natural-Product: Carrier-Free “Triadic” Drug Delivery Platforms for Enhanced Tumor Treatment

Cancer poses a considerable challenge to global public health and stands as the second leading cause of mortality worldwide. Chemotherapy provides limited benefits for advanced-stage cancer, mainly due to high systemic toxicity and drug resistance. Optimal cancer treatment requires a sophisticated, multidisciplinary collaboration aimed at extending survival, enhancing quality of life, and reducing toxicity. Natural products present advantages, including a wide array of structural diversity, reduced toxicity, improved immune modulation, and the ability to act on multiple targets. Nanomedicine design shows promise in tumor treatment and diagnosis by improving efficacy and minimizing side effects. Due to the heterogeneity of tumors in genetics, metabolism, and microenvironment, natural product-based carrier-free drug delivery platforms have been actively investigated and demonstrated considerable potential for enhanced tumor treatment. "Triadic" strategies can simultaneously perform various functions on a carrier-free intelligent nanoplatform. These include combinational chemotherapy, photodynamic therapy (PDT) with bioimaging and chemotherapy, PDT combined with photothermal therapy (PTT) and chemotherapy, chemo-radio-theranostics, as well as gene therapy (GT) in conjunction with PTT and chemotherapy. This multifaceted approach enhances therapeutic efficacy, reduces multidrug resistance, and minimizes systemic toxicity. This review encompasses recent advancements in cancer therapy using carrier-free "triadic" nanomedicines based on natural products (between 2024 and 2025) and evaluates this evolving field, emphasizing the pivotal role of natural products-berberine, camptothecin, hypericin, erianin, curcumin, lactose, paclitaxel, gambogic acid, and glycyrrhizic acid-in drug delivery platforms. Furthermore, it addresses the challenges and bottlenecks encountered by carrier-free drug delivery platforms, offering valuable insights into their development trajectories.