In-situ-formed TCM-inspired dual-function nanocomposite hydrogel for intraoperative hemostasis and postoperative recurrence prevention in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with high postoperative recurrence rates due to occult micrometastases or minimal residual disease, markedly worsening the prognosis for HCC patients. Current therapies lack effective strategies to prevent recurrence, while traditional Chinese medicine (TCM) shows potential in delaying HCC progression. Combining a hemostatic hydrogel with nanoparticle-based delivery of active TCM components provides a strategy to enhance tumor recurrence prevention. Herein, we develop a nanocomposite hydrogel (HPS@ZCJ) by encapsulating Jianpi-Huayu essential oils (JEO) into zein-based nanoparticles (zein@chondroitin sulfate@JEO, ZCJ) and embedding them in a hydroxymethyl cellulose/Pluronic F-127/sodium alginate (HPS) hydrogel matrix. HPS@ZCJ hydrogel enhances cytotoxic T-lymphocyte infiltration, inhibits the polarization of tumor-associated macrophages to M2 phenotype, induces tumor cell death, reverses immunosuppression, and inhibits angiogenesis within the tumor. The antitumor mechanism involves dual downregulation of GPNMB and DHCR7, key genes in HCC progression and immune evasion. In vitro and in vivo experiments demonstrate that HPS@ZCJ hydrogel-mediated targeted comprehensive therapy simultaneously achieves intraoperative hemostasis, impedes primary tumor growth and prevents HCC postoperative recurrence. This study provides a promising postoperative HCC treatment strategy, leveraging TCM's therapeutic potential with significant clinical translation prospects.