Tumor microenvironment-activated and near-infrared light-driven free radicals amplifier for tetra-modal cancer imaging and synergistic treatment

The tumor microenvironment (TME) exhibits a specific feature of hypoxia, which poses significant challenges for oxygen (O₂)-dependent treatments. In this study, we developed an intelligent nanoplatform (PEGylated AIPH@MSN/CDs-MnO₂, denoted as A@M/C-Mn) by integrating a photosensitizer of red carbon dots (CDs) with a thermolabile initiator-loaded mesoporous silica nanoparticle (AIPH@MSN, denoted as A@M), and then growing manganese dioxide nanosheets (MnO₂ NS) in situ and PEGylating the structure to achieve TME-responsive synergistic diagnosis and phototherapy against hypoxic tumors. The outer-layer MnO₂ NS has the capability to decompose endogenous hydrogen peroxide (H₂O₂) in the acidic TME, thereby producing O₂ to alleviate hypoxia while releasing Mn²⁺. This process restores the fluorescence (FL) and photodynamic therapy (PDT) properties of the CDs, enhancing singlet oxygen (¹O₂) generation upon near-infrared (NIR) laser irradiation. Concomitantly, the exposed CDs induce hyperthermia for photothermal therapy (PTT) and promote the decomposition of AIPH to form cytotoxic alkyl radicals (^[rad]R) for O₂-independent PDT. Importantly, the entire treatment process can be monitored through ultrasound (US)/magnetic resonance (MR)/photoacoustic (PA)/FL imaging, owing to O₂ production, Mn²⁺ release, and CDs activation, respectively. Both in vitro and in vivo results provide evidence that A@M/C-Mn represents a promising theranostic nanoagent for hypoxic tumors.