Multifunctional Albumin–MnO₂ Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response

TLDR

Tumor microenvironments are marked by hypoxia, acidosis, and high reactive oxygen species, which drive aggressiveness, metastasis, and therapy resistance, yet current therapies target only one of these factors and lack comprehensive modulation. The study aims to develop multifunctional A‑MnO₂ nanoparticles that simultaneously generate oxygen and raise pH to modulate the tumor microenvironment. These nanoparticles are engineered from a polyelectrolyte–albumin complex and MnO₂, reacting with tumor‑derived H₂O₂ to produce oxygen and neutralize acidity. In a murine breast tumor model, the particles increased tumor oxygenation by 45 %, raised pH from 6.7 to 7.2, downregulated HIF‑1α and VEGF, and when combined with radiation, significantly inhibited tumor growth, enhanced DNA double‑strand breaks, and increased cancer cell death compared to radiation alone.

Abstract

Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H2O2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte–albumin complex and MnO2 nanoparticles (A-MnO2 NPs) and utilized the reactivity of MnO2 toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. In vitro studies showed that these NPs can generate oxygen by reacting with H2O2 produced by cancer cells under hypoxic conditions. A-MnO2 NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO2 NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer.