Modulation of Hypoxia in Solid Tumor Microenvironment with MnO₂ Nanoparticles to Enhance Photodynamic Therapy

TLDR

Tumor hypoxia promotes metastasis and confers resistance to oxygen‑dependent therapies such as photodynamic therapy. The authors designed Ce6‑loaded MnO₂ nanoparticles coated with PEG (Ce6@MnO₂‑PEG) to generate oxygen from tumor‑derived hydrogen peroxide and thereby enhance tumor‑specific photodynamic therapy. MnO₂ reacts with endogenous H₂O₂ to produce O₂, while PEGylation facilitates tumor homing and Ce6 delivery, enabling oxygen‑replenished photodynamic treatment. In vitro and in vivo studies showed that Ce6@MnO₂‑PEG markedly increased intracellular O₂, reduced tumor hypoxia, and achieved superior photodynamic tumor suppression—even at lower drug doses—demonstrating the potential of nanotechnology to overcome hypoxia‑mediated therapy resistance.

Abstract

Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO 2 ) nanoparticles toward endogenous hydrogen peroxide (H 2 O 2 ) within the tumor microenvironment to generate O 2 , multifunctional chlorine e6 (Ce6) loaded MnO 2 nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO 2 ‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO 2 ‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O 2 level benefited from the reaction between MnO 2 and H 2 O 2 , the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO 2 ‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO 2 ‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.