Decreasing the aggregation of photosensitizers to facilitate energy transfer for improved photodynamic therapy.

The mode of energy transfer between photosensitizers and oxygen determines the yield of singlet oxygen (O), crucial for photodynamic therapy (PDT). However, the aggregation of photosensitizers promotes electron transfer while inhibiting pure energy transfer, resulting in the generation of the hypotoxic superoxide anion (O) and consumption of substantial oxygen. Herein, we achieve the reduction of the aggregation of photosensitizers to inhibit electron transfer through classical chemical crosslinking, thereby boosting the production of O. Specifically, we constructed a cross-linked hydrogel-like nanophotosensitizer (HA-TPP NHs) amidation reactions between hyaluronic acid (HA) and tetrakis(4-aminophenyl)porphyrin (TATPP). In HA-TPP NHs, porphyrin is anchored at the crosslinking sites, preventing their close proximity. Simultaneously, HA-TPP NHs swell in a physiological environment due to water absorption, further increasing the distance between porphyrin molecules to avoid their aggregation. Compared to porphyrin-hyaluronic acid assembling nanoparticles (HA-TPP NPs), we find that the O generation efficiency of HA-TPP NHs is elevated by over 80%. Furthermore, leveraging the targeting capabilities of hyaluronic acid, HA-TPP NHs demonstrate a remarkable anticancer effect in and experiments. This study offers a novel insight and method for improving the therapeutic efficacy of PDT.