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.
Acute liver failure (ALF), characterized by severe hepatocyte necrosis with a high mortality rate, remains a major global health challenge. However, there are currently no effective drug options for the clinical treatment of ALF. Herein, inspired by the new concept of a full-API nanodrug (FAND), we have rationally developed a quadruplex bioactive FAND (termed FAND HP@FuEVs ) composed entirely of active pharmaceutical ingredients (APIs). This FAND HP@FuEVs is constructed from fusion extracellular vesicles (FuEVs), which hybridize M2 macrophage-derived EVs (M2–EVs) with mesenchymal stem cell-derived EVs (MSC-EVs) and is subsequently engineered with two clinically therapeutic biomacromolecules: hepatocyte growth factor (HGF) and polyene phosphatidylcholine (PPC). Notably, FAND HP@FuEVs efficiently targets the damaged liver, benefiting from the dual inherent inflammation-tropism of the FuEVs. Moreover, FAND HP@FuEVs harnesses quadruplex biological activities by leveraging four natural bioactive components—M2-EVs, MSC-EVs, HGF, and PPC—to deliver pleiotropic therapies, including antioxidant, anti-inflammatory, pro-regenerative, and macrophage repolarization effects. These therapies are effective in treating ALF induced by both acetaminophen and hepatectomy, demonstrating significant clinical relevance based on data from patients with liver disease. Overall, the utilization of naturally derived or clinically approved APIs to construct full-bioactive nanodrugs creates opportunities for clinical translation as a safe, versatile, and multifaceted treatment for ALF.
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