Carbon dots-based nanoclusters for sonodynamic therapy of bacterial infection enhanced by deep biofilm penetration and hypoxia alleviation

Sonodynamic therapy (SDT) is emerging as a novel and effective treatment modality for antimicrobial applications. However, limited penetration of sonosensitizers and hypoxic infectious microenvironment have significantly restricted the therapeutic efficacy of drug-resistant bacteria. Herein, carbon dots (CDs)-based nanoclusters (MCHH) are facilely constructed by covalent assembly of Mn-doped CDs and simultaneous encapsulation of sonosensitizer hematoporphyrin monomethyl ether (HMME), followed by surface modification with hyaluronic acid (HA). MCHH not only prevents the agglomeration of hydrophobic HMME molecules, but also facilitates their deeper penetration into biofilm. Furthermore, MCHH can be degraded by the overexpressed hyaluronidase in Gram-positive biofilm, resulting in the sustained release of HMME for SDT. Meanwhile, MCHH with catalase-mimic activity contributes to hypoxia alleviation by catalyzing the decomposition of H2O2 into O2. Under ultrasound irradiation, intense SDT can be achieved by MCHH, which is enhanced by its high biofilm permeability and local oxygenation. The proposed strategy produces superb bactericidal effect and realizes admirable biofilm disintegration outcome in vitro. On this basis, MCHH administration on bacterial wound infection model expedites wound healing, benefiting from the synergistic action of biofilm eradication, inflammation suppression, increased collagen decomposition and angiogenesis induction. Taken together, this paradigm provides strategic opinions in augmenting SDT efficacy for anti-infective applications.