Sequential-Delivery Gel Microspheres Integrating HAase-Mediated ECM Remodeling and GA-Active Targeting for Deep Tumor Penetration in TACE-Treated HCC.

Authors

Xuwang Pan, Yunjiang Li, Yidan Shao, Jinsong Huang, Jianhua Yu, Zuhua Chen, Jianfeng Bao, Fanzhu Li, Rangxiao Zhuang

Published in

International journal of nanomedicine. Volume 21. Pages 634549. Epub Sep 30, 2026.

Abstract

Transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) is limited by inadequate intratumoral drug penetration. We developed a sequential-delivery composite gel microsphere system integrating hyaluronidase (HAase)-mediated microenvironment remodeling, glycyrrhetinic acid (GA)-mediated active targeting, and pH-responsive drug release as a potential strategy to address this barrier.
Bufalin (BUF)-loaded GA-PEG-HYD-PLGA nanoparticles and HAase were co-encapsulated within carboxymethyl chitosan/sodium alginate gel microspheres containing BaSO₄ for radiopacity (HAase/BUF NPs-GM). The system was characterized for particle size, drug loading, pH-responsive release, and hemocompatibility. Antitumor efficacy, deep tumor penetration, and mechanisms were evaluated in Huh-7 cells and a rabbit VX2 orthotopic liver tumor model via TACE-guided arterial delivery.
HAase/BUF NPs-GM exhibited a favorable size (270 ± 61.89 μm), pH-dependent BUF release, and good biocompatibility, with an IC_{5 0} of 55.07 nM against Huh-7 cells. The system reduced hyaluronic acid content across all tumor regions, consistent with enhanced penetration of the therapeutic payload into the tumor core. Compared with controls, HAase/BUF NPs-GM combined with TACE suppressed tumor growth and angiogenesis, induced apoptosis, inhibited proliferation, and was associated with increased intratumoral CD3⁺ T cell infiltration and reduced expression of EMT-related markers. Mechanistically, the system induced ROS overproduction, mitochondrial membrane potential decrease, and G2/M cell cycle arrest.
This strategy, which combines microenvironment remodeling, active targeting, and responsive release, provides a promising preclinical proof-of-concept for addressing the penetration limitations of conventional TACE. Further translational investigation, including validation in orthotopic or patient-derived xenograft models and long-term toxicity assessment, is warranted.

PMID:
42831118
Bibliographic data and abstract were imported from PubMed on 05 Oct 2026.

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