Sialic acid–guided spatiotemporal hydrogel therapy for liver cancer

Efficient delivery of plant-derived polyphenolic drugs to tumor sites in hepatocellular carcinoma (HCC) is challenging due to their rapid metabolism and the limited tumor-targeting capacity of current therapeutic strategies. To overcome these limitations, we developed a pH-responsive hydrogel-based drug delivery system (PA-CB) composed of a chitosan backbone functionalized with boronobenzoic acid (CB) and crosslinked with protocatechualdehyde (PA). Within this scaffold, protocatechuic acid (PCA) was incorporated as a model therapeutic agent to demonstrate the platform's ability to achieve controlled, pH-responsive release and to impart anticancer, anti-inflammatory, and antifibrotic effects through the action of the drug. The hydrogel, stabilized via boronate ester and Schiff-base linkages, maintained integrity under physiological conditions while enabling drug markedly enhanced anticancer efficacy in vitro compared to free PCA, including a near-complete reduction of HepG2 cell viability, migration, and colony formation, along with increased apoptosis. This enhanced antitumor efficacy was due to CB-mediated recognition of sialic acid residues on HCC cells, which facilitated tumor-selective accumulation and sustained drug release. Intraperitoneal administration of the hydrogel in an HCC mouse model significantly reduced tumor burden, hepatic inflammation, and fibrosis, while improving liver function markers. Histological assessments confirmed alleviation of liver injury, and quantitative polymerase chain reaction analyses revealed decreased expression of proinflammatory cytokines. Collectively, these results highlight this hydrogel platform as a robust strategy to stabilize phenolic drugs, achieve tumor-targeted delivery, and enable controlled release. These findings highlight its potential as an advanced therapeutic approach for HCC and a versatile framework applicable to other polyphenolic agents in oncology.