Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer

TLDR

Photodynamic therapy is an oxygen‑dependent, light‑triggered, noninvasive cancer treatment that is limited by tumor hypoxia and the localized nature of the therapy. The study aims to develop enzyme‑encapsulated, photosensitizer‑loaded hollow silica nanoparticles that target tumors and mitochondria to enhance photodynamic therapy. These smart nanoreactors feature a pH‑responsive surface coating that retains them in acidic tumors, delivers photosensitizers to mitochondria, and decomposes endogenous H₂O₂ to alleviate hypoxia. In vivo, the nanoparticles improved tumor retention, reduced hypoxia, and when combined with checkpoint blockade, elicited systemic immune responses that eradicated distant non‑irradiated tumors up to 2 cm away.

Abstract

Photodynamic therapy (PDT) is an oxygen-dependent light-triggered noninvasive therapeutic method showing many promising aspects in cancer treatment. For effective PDT, nanoscale carriers are often needed to realize tumor-targeted delivery of photosensitizers, which ideally should further target specific cell organelles that are most vulnerable to reactive oxygen species (ROS). Second, as oxygen is critical for PDT-induced cancer destruction, overcoming hypoxia existing in the majority of solid tumors is important for optimizing PDT efficacy. Furthermore, as PDT is a localized treatment method, achieving systemic antitumor therapeutic outcomes with PDT would have tremendous clinical values. Aiming at addressing the above challenges, we design a unique type of enzyme-encapsulated, photosensitizer-loaded hollow silica nanoparticles with rationally designed surface engineering as smart nanoreactors. Such nanoparticles with pH responsive surface coating show enhanced retention responding to the acidic tumor microenvironment and are able to further target mitochondria, the cellular organelle most sensitive to ROS. Meanwhile, decomposition of tumor endogenous H2O2 triggered by those nanoreactors would lead to greatly relieved tumor hypoxia, further favoring in vivo PDT. Moreover, by combining our nanoparticle-based PDT with check-point-blockade therapy, systemic antitumor immune responses could be achieved to kill nonirradiated tumors 1–2 cm away, promising for metastasis inhibition.