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

Abstract The heavy dependence on intratumoral O 2 and H 2 O 2 availability has greatly restricted ROS‐based therapy. Although O 2 /H 2 O 2 ‐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 Fe 3+ , and FDA‐approved fluorescent agent ICG for hypoxic tumor therapy are rationally designed and constructed. Attractively, the completely pharmaceutically active components ARTE, Fe 3+ , and ICG can be responsively liberated in the acidic tumor microenvironment and synergistically produce five types of free radicals including •O 2 − , •C, •OH, LOO•, and 1 O 2 , 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.