A Multimodal Energy-Depletion Strategy for Cooperative Tumor Metabolism Regulation in Enhanced Cancer Therapy

Metabolic reprogramming represents a defining feature of the tumor microenvironment, driving both unchecked proliferation and therapeutic resistance. While conventional single-target metabolic therapies have demonstrated limited efficacy owing to the intrinsic adaptability of tumor cells, recent attention has turned toward natural herbal medicine. Combining broad, multilayered actions with low toxicity, they offer a promising way to modulate tumor metabolism and overcome current therapeutic limits. Herein, this work introduces an Artesunate/Icaritin (ART/ICA) hybrid nanoplatform derived from herbal medicine that employs a multimodal energy depletion strategy for malignant tumor therapy. Coadministration of ICA and ART in a nano-platform produces a mutually reinforcing effect that amplifies inhibition of glucose uptake, strengthens antiangiogenic activity, and intensifies mitochondrial dysfunction, overcoming the limitations of single-pathway interventions. The glutathione-responsive disulfide linkages in the nanomedicine enabled controlled, tumor-selective drug release, enhancing the therapeutic agents' stability and bioavailability. In vitro mechanistic studies supported by RNA sequencing analyses and traditional molecular assays demonstrated that this multimodal approach effectively disrupted cellular energy homeostasis, induced apoptosis, and regulated key metabolic pathways. In vivo evaluations using various tumor models, including hepatocellular carcinoma transgenic mouse models, confirmed significantly enhanced antitumor efficacy, while subcutaneous tumor models showed a tumor inhibition rate exceeding 97%, far surpassing the effects of ART or ICA alone. Furthermore, flow cytometry analyses also confirmed that this strategy modulated the tumor microenvironment by enhancing the infiltration of cytotoxic CD8⁺ T cells and promoting dendritic cell maturation, while the incorporation of a CD47-targeting nanobody further strengthened immune activation and contributed to improved antitumor efficacy.