Bio-inspired fractal-structured gel-drugs enable enhancing deep tumor penetration for efficient chemotherapy of hepatocellular carcinoma.

Current nanoparticle-based drug delivery systems present significant challenges in treating solid tumors, primarily due to a variety of physiological and pathological barriers that hinder the deep penetration of drugs. Herein, we demonstrate bio-inspired fractal-structured gel-drugs (DOX@HPLA, DHPL) that significantly enhance deep tumor penetration, thereby greatly improving the chemotherapy efficiency for hepatocellular carcinoma (HCC). The fabrication of DHPL is achieved through a crosslinking of 8-arm polyethylene glycol (PEG) and polysaccharide heparin in the presence of DOX, which is subsequently modified with targeting lactobionic acid (LA). During the process of penetration, these fractal-structured gel-drugs could leverage their soft and rough surfaces endowed by their unique fractal structures to increase the interfacial contact sites with the tumor cells through topographic interactions, which optimizes the cell adhesion in the local area. This results in a significant enhancement of interfacial adhesion and internalization, thereby substantially improving receptor-mediated endocytosis associated with subsequent transcytosis. In the process of transcytosis, the fractal-structured gel-drugs facilitate the early endosomes/recycling endosomes pathway for exocytosis and concurrently diminish degradation in the early endosomes/late endosomes/lysosome pathway, resulting in deeper tumor penetration and thereby enhancing the chemotherapy efficiency for HCC. It is believed that the bio-inspired fractal-structured gel-drugs enable efficient amplification of interfacial interactions with cells through fractal-structure-mediated topographic interactions, providing an avenue for deep penetration treatment of solid tumors.