Liu Heng,Liu Yu,Chu Chengchao,Tong Haipeng,Xue Wei,Wang Junqing,Liu Gang,Zhang Weiguo
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.
A self-assembling nanoplatform based on FOB (a heteropolysaccharide from Fomitopsis officinalis ) named QU@FOB-FcDBA was developed in this study. A dynamic boronate ester bond, a pH-sensitive covalent linkage formed through reversible dehydration reactions, linked FOB and 1,1′-ferrocenediboronic acid (FcDBA) while encapsulating the hydrophobic drug quercetin (QU). The formulation not only enhanced the water solubility of QU, but also indirectly improved the clinical utilization rate of QU. QU@FOB-FcDBA exhibited unique dual pH/ROS-responsive characteristics, enabling precise recognition and selective response to the acidic microenvironment and elevated reactive oxygen species (ROS) levels in tumor tissues. This ensured the accurate and controlled release of QU and FcDBA, achieving synergistic deep penetration and enhanced therapeutic efficacy through the combined induction of ferroptosis and chemotherapy. In vivo , QU@FOB-FcDBA effectively suppressed tumor progression and metastasis. Mechanistically, it induced cell death via multiple pathways: triggering ferroptosis through ROS accumulation, lipid peroxidation (LPO), and glutathione (GSH) depletion, as well as inducing apoptosis. In vitro , FOB upregulated macrophage surface markers (CD40, CD80, CD86, MHC-II) and nitric oxide (NO) expression. This innate immune activation may directly contribute to antitumor effects and establish a favorable immune microenvironment for immunotherapy. These results position QU@FOB-FcDBA as a promising platform integrating ferroptosis induction and chemotherapy for improved cancer treatment.
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