Heparosan-based amphiphilic nanomicelles for photodynamic antitumor therapy

Conventional phthalocyanine photosensitizers in photodynamic therapy (PDT) are often hindered by poor aqueous solubility and inadequate tumor selectivity. To address these limitations, we developed tumor-targeted heparosan nanomicelles (HDZ), in which tetraamino zinc phthalocyanine (TAZnPc) is covalently conjugated to DBCO-modified heparosan (HD). Heparosan (HP)-the unsulfated K5 capsular polysaccharide and biosynthetic precursor of heparin-was selected as the carrier due to its resistance to heparanase-mediated degradation, alongside its inherent biodegradability and biocompatibility. The HDZ system leverages metabolic glycoengineering and bioorthogonal click chemistry for active tumor targeting. The optimized HDZ micelles (~136.6 nm) exhibited a TAZnPc content of 17.2% (w/w). In vitro, HDZ elevated intracellular ROS generation in a light-dependent manner and reduced A549 cell viability by ~70% at an equivalent TAZnPc concentration of 10 μM. In vivo, the Ac₄ManNAz-pretreated HDZ group achieved an 82.4% tumor inhibition rate, significantly outperforming the HDZ-alone group (68.2%; P < 0.001) without inducing obvious short-term toxicity. Collectively, within the conditions evaluated in this study, the HDZ nanoplatform improved the efficacy of TAZnPc-mediated PDT by integrating a heparosan-based carrier with bioorthogonal two-step targeting; however, its general applicability and potential in precision oncology remain to be validated in additional tumor models and with direct biodistribution evidence.