Quintuple Free-Radical Therapy: An Ultralong-Retention FAND for NIR-Involved Multiple Site-Acting Hypoxic Tumor Therapy

The heavy dependence on intratumoral O₂ and H₂O₂ availability has greatly restricted ROS-based therapy. Although O₂/H₂O₂-irrelevant free-radical nanogenerator has garnered tremendous attention as a promising anticancer candidate to overcome the above intrinsic limitations of ROS-based treatment, the practical therapeutic efficacy of free-radical therapy is still hindered by limited free-radical type and inferior tumor retention performance. Herein, inspired by the new concept of full-API nanodrug (FAND) with 100% active pharmaceutical ingredient (API) content and repurposing of clinical anti-malaria drug artesunate (ARTE) as an anticancer free-radical generator, the AFeI FANDs composed of ARTE, human essential Fe³⁺, and FDA-approved fluorescent agent ICG for hypoxic tumor therapy are rationally designed and constructed. Attractively, the completely pharmaceutically active components ARTE, Fe³⁺, and ICG can be responsively liberated in the acidic tumor microenvironment and synergistically produce five types of free radicals including •O₂⁻, •C, •OH, LOO•, and ¹O₂, leading to robust mitochondrial injury, nuclear DNA damage, and lipid peroxides. More importantly, the AFeI FANDs displayed ultralong tumor retention longer than 108 h and favorable tumor suppression outcomes under mild NIR irradiation. Collectively, the presented first paradigm of FAND-based quintuple free-radical therapy expands new horizons for the development of clinically transferable nanomedicine for tumor therapy.