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Background <p>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.</p> Methods <p>The construction, physical stability, biocompatibility and targeting capability of PLP-II/MGlu-Curd-Lips were evaluated using <sup>1</sup>H NMR spectra, FT-IR spectroscopy, TEM, LUMiSizer assay, CCK-8 assay, Flow Cytometry (FC), and IVIS imaging. Therapeutic efficacy was assessed through FC, H&amp;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.</p> Results <p>A Dectin-1-targeted pH-responsive liposomal nanoplatform (PLP-II/MGlu-Curd-Lips) was developed for spatiotemporally controlled delivery of <i>Plantago asiatica</i> 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.</p> Conclusions <p>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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月1日

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  • Wanbing Pan,
  • Can Li,
  • Xiaoyu Zhou,
  • Wei Liu,
  • Jintong Liu,
  • Qiao Lin,
  • Jinglin Huang,
  • Zhihui Hao,
  • Yanyan Jiang,
  • Jiahao Lin

摘要

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.

Graphical abstract