H2O2‐Activatable Liposomal Nanobomb Capable of Generating Hypoxia‐Irrelevant Alkyl Radicals by Photo‐Triggered Cascade Reaction for High‐Performance Elimination of Biofilm Bacteria

Abstract High H 2 O 2 levels are widely present at the infection sites or in the biofilm microenvironment. Herein, hemin with peroxidase‐like catalytic activity and its substrate, 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), are simultaneously introduced into a liposomal nanoparticle containing thermosensitive 2,2′‐azobis[2‐(2‐imidazolin‐2‐yl) propane] dihydrochloride (AIBI)‐loaded bovine serum albumin (BAG), rationally constructing an H 2 O 2 ‐activatable liposomal nanobomb (Lipo@BHA) for combating biofilm‐associated bacterial infections with high performance. In the presence of H 2 O 2 , hemin can catalyze the conversion of ABTS into its oxidized form (ABTS· + ) with strong near‐infrared (NIR) absorption, which produces photonic hyperpyrexia to cause the decomposition of AIBI into oxygen‐independent alkyl radicals (·R) and nitrogen (N 2 ) microbubbles. The former not only directly damage bacterial cells but also significantly accelerates the oxidization of ABTS to ABTS· + for augmenting photothermal‐triggered generation of ·R. Interestingly, the released N 2 can induce transient cavitation to rupture lysosomal nanoparticle and improve the biofilm permeability, thereby enhancing the antibiofilm effect of Lipo@BHA. The proposed Lipo@BHA exhibits satisfactory multi‐mode combination antibacterial properties. Through endogenous H 2 O 2 ‐activated cascade reaction, Lipo@BHA achieves remarkable hypoxia‐irrelevant ·R therapy of biofilm‐associated wound infections with low cytotoxicity and good in vivo biosafety. Therefore, this work presents a versatile H 2 O 2 ‐activatable cascade ·R generation strategy for biofilm‐specific therapeutic applications.