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Synergistic chemo-immunotherapy for osteosarcoma via a pH-responsive multi-component nanoparticle system.

Dapeng Li1,2, Yuanfan Li1,2, Jie Cang1

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A novel nanoparticle system co-delivers chemotherapy and immune activators to effectively treat osteosarcoma by inducing immunogenic cell death and enhancing anti-tumor immunity, reducing toxicity.

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TLR4 and STING agonistsimmunogenic cell deathosteosarcomapH-responsive immune-modulating nanoparticlestumor microenvironment reprogramming

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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Immunotherapy

Background:

  • Osteosarcoma (OS) is a common pediatric bone cancer with challenging treatments due to chemotherapy toxicity and poor induction of immunogenic cell death (ICD).
  • Current therapeutic strategies for osteosarcoma often suffer from limited efficacy and significant side effects.

Purpose of the Study:

  • To develop and optimize a pH-responsive, multi-component nanoparticle system for co-delivery of doxorubicin (DOX), monophosphoryl lipid A (MPLA), and a PD-1/PD-L1 targeting peptide.
  • To evaluate the therapeutic efficacy of this nanoparticle system in an orthotopic osteosarcoma model.

Main Methods:

  • A pH-responsive nanoparticle system was engineered to co-deliver DOX, MPLA, and a PD-1/PD-L1 targeting peptide, integrated with PEG-PC7A.
  • Optimization was performed using one-factor-at-a-time (OFAT) and Box-Behnken design (BBD).
  • In vitro and in vivo studies were conducted to assess ICD markers, immune cell activation, tumor suppression, and immune memory.

Main Results:

  • Optimized nanoparticles (110 nm) demonstrated high encapsulation efficiency (97.15%) and pH-sensitive release (91% at pH 6.5).
  • In vitro studies showed enhanced ICD markers and synergistic dendritic cell maturation via STING/TLR4 activation.
  • In vivo, the nanoparticles significantly suppressed tumor growth, increased cytotoxic T lymphocyte infiltration, reduced regulatory T cells, and established long-term immune memory.

Conclusions:

  • The multifunctional nanoparticle platform effectively induces immunogenic cell death, activates innate immunity, and provides checkpoint blockade for osteosarcoma.
  • This immunochemotherapeutic strategy demonstrates significant potential for enhanced therapeutic efficacy and reduced systemic toxicity in osteosarcoma treatment.