Biofilm microenvironment response nanoplatform synergistically degrades biofilm structure and relieves hypoxia for efficient sonodynamic therapy

[Display omitted] •MAPC as a novel biofilm microenvironment-responsive nanoplatform can decompose in the acidic biofilm microenvironment and subsequently releases the α-amylase, manganese oxide and sonosensitizer.•MAPC released α-amylase can selectively degrade the extracellular polymeric substances of MRSA biofilms and further promotes the sonosensitizer penetration.•MAPC released manganese oxide with catalase-like activity can convert the overproduced H2O2 into O2 to relieve the hypoxic biofilm microenvironment, which significantly enhances the sonodynamic antimicrobial efficiency.•MAPC offers an effective therapeutic strategy for superior MRSA biofilm eradication efficiency of combining biofilm structure degradation with improved ultrasound-driven antimicrobial sonodynamic therapy by hypoxia relief. Treatment of bacterial biofilms remains a great challenge in the clinic. Recently, ultrasound (US)-driven antimicrobial sonodynamic therapy (aSDT) has been considered as an emerging therapeutic strategy for the treatment of biofilm infections. However, the hypoxic microenvironment and restricted diffusion of sonosensitizers within biofilms substantially reduce the therapeutic efficacy of aSDT. Herein, a biofilm microenvironment-responsive nanoplatform was proposed to promote biofilm degradation and sonosensitizer penetration, and relieve the hypoxic microenvironment, thereby augmenting aSDT efficiency against bacterial biofilm infections. This nanoplatform was prepared by modifying manganese dioxide nanosheets (MNS) with α-amylase, polyethylene glycol (PEG), and chlorin e6 (Ce6) to form MNS-α-amylase/PEG-Ce6 nanosheets (MAPC). After delivery into biofilm-infected tissues, MAPC decompose in the acidic biofilm microenvironment to locally release α-amylase and Ce6. The α-amylase degrades the extracellular polymeric substances of biofilms to promote Ce6 penetration. In addition, the MNS catalyze the conversion of endogenously overproduced H2O2 into O2 in infected tissue and relieve the hypoxic microenvironment to further enhance antibiofilm efficacy of aSDT. Such biofilm degradation and hypoxia-relief enhanced aSDT show approximately 6.9 log units (99.99998%) reduction of bacteria within biofilms in vitro, and efficiently treat methicillin-resistant Staphylococcus aureus (MRSA) biofilms-infected mice. Overall, biofilm degradation improves sonosensitizer penetration and relieves the hypoxic biofilm microenvironment to enhance the effects of aSDT by MAPC. Thus, th