Mitochondrial Glutathione Depletion Nanoshuttles for Oxygen-Irrelevant Free Radicals Generation: A Cascaded Hierarchical Targeting and Theranostic Strategy Against Hypoxic Tumor

An oxygen-irrelevant free radicals generation strategy has shown great potential in hypoxic tumor therapy. However, insufficient tumor accumulation, nonspecific intracellular localization, and the presence of highly reductive mitochondrial glutathione (GSH) dramatically hamper the free radicals therapeutic efficacy. Herein, a hierarchical targeting system was constructed by Fe-doped polydiaminopyridine nanoshuttles, indocyanine green (ICG), and an oxygen-irrelevant radicals generator (AIPH) to possess a negative charge. An acid-specific charge-reverse capability of the shuttles was achieved to enhance cell uptake in the tumor microenvironment (TME). In addition, the iron release occurs only in the acidic TME, which can be used as acidity enhancers to strengthen the charge-reverse process, thereby leading to more efficient tumor internalization and deep penetration. Moreover, such a nanosystem has significantly improved the delivery efficiency of nanoshuttles (16.06%) in the tumor tissues at 24 h postinjection, much higher than that of naked Fe-doped polydiaminopyridine (6.59%). More importantly, the nanoshuttles enable simultaneously mitochondria targeting and corresponding GSH depleting capability to show advantages in free radicals-based therapy after charge reversion, leading to a powerful tumor inhibition rate (>95%). The prescence of iron could allow for magnetic resonance imaging, while ICG allowed for photoacoustic imaging and fluorescence imaging to guide the therapeutic process. The remarkable features of the nanoshuttles may open a new avenue to explore an oxygen-irrelevant free radicals generating system for accurate cancer theranostics.