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Synergistic Provoking of Pyroptosis and STING Pathway by Multifunctional Manganese-Polydopamine Nano-Immunomodulator

Yufei Du1, Yiyin Mai1, Zhiwen Liu1,2

  • 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.

Advanced Healthcare Materials
|May 21, 2025
PubMed

Insights

Manganese ions boost anti-tumor immunity. New nanoparticles precisely deliver manganese to tumors, activating immune cells and killing cancer cells, offering a promising treatment for renal cell carcinoma.

Area of Science:

  • Biomedical Engineering
  • Immunology
  • Oncology

Background:

  • Manganese ions activate anti-tumor immunity via the cGAS-STING pathway.
  • Precise manganese delivery to the tumor microenvironment is challenging.
  • Metastatic renal cell carcinoma (RCC) requires novel therapeutic strategies.

Purpose of the Study:

  • To develop a multifunctional nano-immunomodulator for targeted manganese delivery and enhanced anti-tumor immunity in RCC.
  • To investigate the mechanisms of nanoparticle-mediated immune activation and tumor cell death.

Main Methods:

  • Synthesized manganese-polydopamine nanoparticles coated with hyaluronic acid (PDA-Mn-HA NPs).
  • Utilized CD44 targeting for selective binding to tumor-associated macrophages and RCC cells.
  • Analyzed macrophage polarization, cytokine/chemokine production, and signaling pathways (ROS-STING-p38/MAPK).
  • Investigated ROS-caspase-3/GSDME-dependent pyroptosis in RCC cells.
  • Evaluated therapeutic efficacy in RCC mouse models.

Main Results:

  • PDA-Mn-HA NPs demonstrated tumor microenvironment-responsive manganese release.
  • Treatment induced M1 macrophage polarization and pro-inflammatory cytokine production.
  • Nanoparticles activated macrophages via the ROS-STING-p38/MAPK pathway.
  • PDA-Mn-HA NPs induced pyroptosis in RCC cells through ROS generation.
  • In vivo studies showed suppressed tumor growth and enhanced immune cell infiltration.

Conclusions:

  • Multifunctional PDA-Mn-HA NPs offer precise manganese delivery for cancer immunotherapy.
  • Synergistic targeting of macrophages and tumor cells provides a promising therapeutic strategy for RCC.
  • This approach addresses limitations in manganese delivery and enhances anti-tumor immunity.
Keywords:
cGAS‐STINGmanganesenano‐immunomodulatorpyroptosisrenal cell carcinoma

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