Intelligent Albumin-Stabilized Manganese Dioxide Nanocomposites for Tumor Microenvironment Responsive Phototherapy

The aberrant tumor microenvironment (TME) characterized by hypoxia and acidification is closely associated with tumor malignant phenotypes and treatment resistance. Designing biocompatible TME-responsive nanoagents via convenient fabrication procedures are of particular interest for specific and effective tumor theranostics. In this work, bovine serum albumin stabilized manganese dioxide (MnO2) nanostructures (BMnNSs) were synthesized via an environmental-friendly and facile one-step biomineralization process at physiological temperature, which possess suitable size, good water dispersibility, and excellent biocompatibility. Then, the photosensitizer 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide (HPPH) was anchored onto BMnNSs with desirable loading efficiency, obtaining multifunctional BMnNSs-HPPH nanocomposites (BMnHNCs). The high reactivity of MnO2 towards acidic pH/hydrogen peroxide (H2O2) was utilized to achieve TME responsive near-infrared fluorescence/magnetic resonance dual-modal imaging and improved photodynamic therapy. Owing to the efficient tumor accumulation of BMnHNCs mediated by the passive targeting effect and generated oxygen in situ resulting from the reaction between MnO2 and endogenous H2O2 in tumor cells, the BMnHNCs exhibited remarkably enhanced tumor growth suppression compared with HPPH. Furthermore, tumor hypoxia and the vascular endothelial growth factor expression were effectively attenuated by BMnHNCs. Notably, the BMnHNCs demonstrated no apparent in vivo toxicity upon intravenous administration. This biocompatible and biodegradable nanoformulation holds great potential for TME modulation and improved tumor theranostics for clinical translation.