Dectin-1-targeted pH-responsive liposomal nanoplatform delivering Plantago Asiatica L. acidic polysaccharide for immunomodulation and immunosuppressive breast cancer microenvironment reprogramming.

Abstract

Background: The limited tumor-specific delivery and insufficient dendritic cell (DC) activation remain critical challenges in cancer immunotherapy. This research aimed to improve antitumor efficacy by developing a novel pH-responsive liposomal nanoplatform that specifically targets DC via Dectin-1 recognition in the tumor microenvironment (TME), thereby enhancing cellular immunity, minimizing off-target toxicity and reprograming the tumor immunosuppressive TME.

Methods: The construction, physical stability, biocompatibility and targeting capability of PLP-II/MGlu-Curd-Lips were evaluated using ¹H NMR spectra, FT-IR spectroscopy, TEM, LUMiSizer assay, CCK-8 assay, Flow Cytometry (FC), and IVIS imaging. Therapeutic efficacy was assessed through FC, H&E staining, TUNEL, and immunohistochemical staining. The antitumor mechanism of action of PLP-II/MGlu-Curd-Lips in murine 4T1 breast tumors was investigated using RNA sequencing.

Results: A Dectin-1-targeted pH-responsive liposomal nanoplatform (PLP-II/MGlu-Curd-Lips) was developed for spatiotemporally controlled delivery of Plantago asiatica L. acidic polysaccharide (PLP-II). The nanocarrier featured a curdlan-grafted copolymer backbone with pH-cleavable 3-methyl glutarylated moieties and demonstrated an ideal particle size and enhanced stability, enabling tumor acidity-triggered payload release, Dectin-1-mediated DC targeting, and enhanced cytoplasmic delivery via lysosomal escape. The prepared nanocarriers exhibited obvious lysosomal accumulation, and they significantly improved the co-stimulation and migration ability of DCs. In vivo studies indicated that the PLP-II/MGlu-Curd-Lips accumulated at the tumor sites and efficiently promoted DCs activation, tumor-associated macrophages (TAMs) polarization, and cytotoxic T lymphocytes (CTLs) infiltration. Consequently, this remodeling of the tumor microenvironment significantly inhibited the growth of 4T1 breast tumors. Importantly, RNA-Seq confirmed that this therapeutic approach promoted the upregulation of genes related to p53 and NF-κB signaling pathways, thereby enhancing immune activation and tumor-suppression effect.

Conclusions: This study establishes curdlan-modified liposomes as the dual-functional nanoplatform that synergistically enhances DC-targeted delivery of PLP-II and systemic immune activation, providing a promising strategy to augment cancer immunotherapy.