Study on the inhibition of liver cancer progression by lenvatinib nanoparticles combined with hyaluronic acid/gelatin scaffold.

Hepatocellular carcinoma (HCC) remains a leading cause of malignancy-related mortality worldwide, primarily due to the high incidence of postoperative recurrence and the absence of standardized adjuvant therapeutic protocols. While lenvatinib (LT) is established as a first-line targeted therapy for advanced HCC, its clinical efficacy is frequently compromised by poor aqueous solubility and significant systemic adverse effects. To bridge this therapeutic gap, we developed a dual-functional nano-delivery platform, designated as Gel@LTNPS, which integrates rapid localized hemostasis with sustained, targeted antitumor activity for postoperative wound management. In this study, pH-sensitive nanoparticles (LTNPS) were successfully fabricated using the amphiphilic copolymer PAE-PEG-NH2 via ultrasonic emulsification, achieving a high drug loading (DL) rate of 38.9% and an encapsulation efficiency (EE) of 73.9%. These nanoparticles were subsequently incorporated into a gelatin/hyaluronic acid (Gel-HA) hydrogel scaffold through covalent cross-linking. Physicochemical analysis demonstrated that LTNPS exhibit highly sensitive pH-dependent release kinetics, with 67.3% of LT released at a pH of 5.5 (simulating the acidic tumor microenvironment) compared to only 18.3% at physiological pH 7.4 within 96 h. The optimized Gel@LTNPS formulation (containing 15% gelatin) exhibited superior swelling properties, a controlled biodegradation profile of 21 days, and a robust compressive strength of 0.13 MPa, satisfying the mechanical prerequisites for surgical applications. Functional evaluations in mouse tail-bleeding models confirmed that Gel@LTNPS significantly expedited the coagulation process and minimized blood loss, demonstrating hemostatic performance equivalent to clinical-grade gelatin. Furthermore, in vitro and in vivo assays against H22 HCC models revealed that the platform effectively suppressed tumor cell viability and inhibited proliferation, as evidenced by a marked reduction in proliferating cell nuclear antigen (PCNA) expression. Crucially, the platform exhibited an excellent biosafety profile, with no observable systemic toxicity or histopathological damage to major organs. Collectively, this study offers a sophisticated strategy for the postoperative management of HCC by combining localized wound care with microenvironment-responsive chemotherapy, presenting significant potential for clinical translation.