ROS-responsive self-assembly nanoplatform overcomes hypoxia for enhanced photodynamic therapy.

Photodynamic therapy (PDT) has emerged as a promising treatment for malignant tumours in recent decades due to its impressive spatiotemporal selectivity, minimal invasiveness, and few adverse effects. Despite these advancements, there remain significant challenges in effectively delivering photosensitizers to tumours and overcoming tumour hypoxia to maximize the therapeutic benefits of PDT. Ongoing research efforts are focused on developing innovative strategies to overcome the above-mentioned challenges, such as nanoplatforms and combination therapy approaches. Hence, reactive oxygen species (ROS)-responsive polymeric micelles are promising candidates to enhance the distribution and retention of photosensitizers within tumours. Additionally, efforts to alleviate tumour hypoxia may further improve the anti-tumour effects of PDT. In this study, we designed ROS-responsive polymeric micelles (TC@PTP) co-loaded with a Tapp-COF, a porphyrin derivative, and capsaicin for PDT of melanoma. These ROS-responsive nanocarriers, constructed from thioketal (TK)-linked amphiphilic di-block copolymers (PEG5K-TK-PLGA5K), could accumulate in the tumor microenvironment and release drugs under the action of ROS. Capsaicin, acting as a biogenic respiratory inhibitor, suppressed mitochondrial respiration and the hypoxia-inducible factor 1 (HIF-1) signaling pathway, thereby increasing oxygen levels at the tumour site. These PDT-triggered ROS-responsive nanoparticles effectively alleviated the tumour hypoxic microenvironment and enhanced anti-tumour efficacy. With superior biocompatibility and tumour-targeting abilities, the platform holds great promise for advancing anti-tumour combination therapy.