Carrier-free multifunctional nanomedicine for enhanced hyperthermic intraperitoneal chemotherapy against abdominal pelvic tumors

Hyperthermic intraperitoneal chemotherapy (HIPEC) as an innovative approach in cancer therapy can deliver heated drugs directly into the abdominal cavity. Nevertheless, HIPEC also promotes upregulation of heat shock proteins, potentially leading to resistance against hyperthermia. Herein, novel nanoparticles self-assembled from gambogic acid (GA) and metformin (Met) are prepared through multiple interactions, enabling HIPEC for the treatment of orthotopic colorectal and ovarian cancers. Briefly, mild heat (abbreviated as MH) triggers immunogenic cell death (ICD) of cancer cells, leading to the release of damage-associated molecular patterns (DMAPs) that boost the immunogenicity of tumor microenvironment. GA, a potent inhibitor of heat shock protein (HSP-90), increases the sensitivity of cancer cells to hyperthermia-induced cell death. Moreover, GA acts as a chemotherapeutic agent itself, effectively inducing apoptosis of cancer cells and amplifying the ICD induced by MH. Met, can efficiently clear the tumor extracellular matrixes to facilitate the deeper penetration of nanoparticles into tumor tissues and promotes the infiltration of cytotoxic T lymphocytes. More importantly, the synergistic combination of GA and Met during HIPEC triggers a robust anti-tumor immune response in vivo. This integrated strategy offers a promising therapeutic avenue for the management of advanced abdominal pelvic tumor, possessing the potential for broad clinical applications.