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A comprehensive immune cycle enhancement strategy for alternative splicing-mediated endogenous Tumor neoantigens

Linbang Wang1, Yu Liu1, Ziyu Wang1

  • 1Department of Orthopedics, Peking University Third Hospital, Beijing, People's Republic of China.

Materials Today. Bio
|September 22, 2025
PubMed

Insights

A novel nanoparticle system, BI@PCM NPs, effectively targets osteosarcoma by generating high-quality endogenous tumor neoantigens and enhancing immune responses. This approach shows promise for overcoming limitations in current cancer immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Nanotechnology
  • Materials Science

Background:

  • Conventional immunotherapies struggle to eradicate osteosarcoma due to low neoantigen immunogenicity and incomplete immune cycle activation.
  • Existing strategies often target only one step of the tumor immunity cycle, limiting comprehensive antitumor responses.

Purpose of the Study:

  • To develop an innovative core-shell nanoparticle system, BaTiO3-indisulam@PD1-cell Membrane Nanoparticles (BI@PCM NPs), for enhanced osteosarcoma immunotherapy.
  • To address the limitations of conventional approaches by generating high-quality endogenous tumor neoantigens (ETNs) and stimulating a comprehensive immune response.

Main Methods:

  • Developed BI@PCM NPs with BaTiO3 nanocubes for ETN transport and ultrasound-triggered component release.
  • Utilized BI@PCM NPs to disrupt alternative RNA splicing for ETN generation, bypassing DNA damage-mediated pathways.
  • Incorporated BaTiO3 as a piezoelectric catalyst for ROS production and enhanced immunogenic cell death.
  • Employed PD1 cell membrane coating for improved tumor targeting and cytotoxic T-cell activation.

Main Results:

  • BI@PCM NPs successfully generated high-quality ETNs and facilitated their transport to lymph nodes.
  • Ultrasound stimulation of BaTiO3 generated ROS, leading to enhanced immunogenic death of osteosarcoma cells.
  • The PD1 cell membrane coating improved targeting and significantly amplified cytotoxic T-cell responses.
  • The nanoparticle system effectively strengthened multiple steps of the tumor immunity cycle.

Conclusions:

  • BI@PCM NPs represent a promising strategy for overcoming osteosarcoma's low immunogenicity and enhancing antitumor immunity.
  • This innovative approach has the potential to revolutionize personalized tumor immunotherapy for osteosarcoma treatment.
Keywords:
BaTiO3 nanocubesEndogenous Tumor neoantigensOsteosarcomaProgrammed cell death-1RNA alternative splicing

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