Acidic TME‐Responsive Nano‐Bi₂Se₃@MnCaP as a NIR‐II‐Triggered Free Radical Generator for Hypoxia‐Irrelevant Phototherapy with High Specificity and Immunogenicity

Abstract Here, acidic tumor microenvironment (TME)‐responsive nano‐Bi₂Se₃@MnCaP, as a near‐infrared‐II (NIR‐II) biowindow‐triggered free radical generator for hypoxia‑irrelevant phototherapy, is elaborately developed by biomimetic mineralization of MnCaP onto 2, 2′‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH)‐loaded mesoporous nano‐Bi₂Se₃ to form Bi₂Se₃/AIPH@MnCaP (BAM). Surface mineral of MnCaP can be degraded under mild acidity, leading to the release of both Mn²⁺ and AIPH. The leached Mn²⁺ not only facilitates chemodynamic therapy (CDT) via hydroxyl radicals (^•OH) from Mn²⁺‐mediated Fenton‐like reaction but also acts as contrast agent for magnetic resonance imaging. In another aspect, the splendid photothermal conversion capacity of BAM enables a rapid hyperthermia generation under NIR‐II laser irradiation for photothermal therapy (PTT). Simultaneously, the local thermal shock can induce the disintegration of AIPH to generate alkyl radicals (^•R) for thermodynamic therapy (TDT) and accelerate Fenton‐like reaction rate to augment CDT efficacy. The strong synergistic effects from cooperative CDT/PTT/TDT are applied to 4T1 tumor suppression with minimal side effects. Importantly, the combination therapy can effectively trigger immunogenetic cell death and enhance antitumor immunity for systemic tumor eradication. Collectively, this proof‐of‐concept study demonstrates a more efficacious and safer strategy for oxygenation‐independent phototherapy, which holds a good potential for clinical translation in cancer management.