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 (¹O₂), 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 (O₂^-) 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 ¹O₂. Specifically, we constructed a cross-linked hydrogel-like nanophotosensitizer (HA-TPP NHs) via 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 ¹O₂ 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 in vitro and in vivo experiments. This study offers a novel insight and method for improving the therapeutic efficacy of PDT.