Localized hydrogel delivery of photoactivatable mRNA lipid nanoparticles and hyaluronidase for postoperative TNBC immunotherapy.

Authors

Ao Hoi Tong, Haichao Zhu, Chenming Zou, Bingshu Liang, Xueer Wu, Shengrong Guo

Published in

International journal of biological macromolecules. Pages 154367. Sep 06, 2026. Epub Sep 06, 2026.

Abstract

Triple-negative breast cancer (TNBC) responds poorly to immunotherapy, in part because its hyaluronic acid (HA)-rich and immunosuppressive tumor microenvironment restricts drug penetration and antitumor immune activation. Here, we developed an injectable alginate hydrogel platform (ICG-LNP@ALG-H) for localized co-delivery of hyaluronidase (HAase) and indocyanine green (ICG)-functionalized lipid nanoparticles (LNPs) carrying messenger RNA (mRNA) encoding interleukin-12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF). After administration into the postoperative tumor bed, the hydrogel formed an in situ depot that enabled sustained local retention and release. HAase degraded the HA-rich stromal matrix to enhance nanoparticle penetration, while near-infrared (NIR)-activated ICG generated reactive oxygen species through a photodynamic effect, promoting endosomal escape and improving intracellular mRNA delivery and cytokine expression. This platform integrated stromal remodeling, photoactivated intracellular delivery, and local immunostimulation in a single controlled-release system. In a postoperative 4 T1 TNBC recurrence model, ICG-LNP@ALG-H reduced local recurrence and elicited coordinated local and systemic immune responses, as indicated by enhanced intratumoral IL-12 expression and CD8+ T-cell infiltration, together with increased splenic NK-cell frequency, dendritic-cell maturation, and M1-like macrophage polarization. Short-term safety assessments revealed no overt abnormalities under the tested conditions. These results show that localized delivery of matrix-remodeling and immunostimulatory cargoes can address both stromal and intracellular barriers to mRNA therapy, supporting ICG-LNP@ALG-H as a locoregional controlled-release strategy for postoperative immunotherapy of stromal-rich solid tumors.

PMID:
42702319
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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