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RAP-peptide functionalized biomimetic nanoformulation with pathological ROS/pH-responsive drug release for target

Yunfan Li1,2, Kaiwen Bao1,2, Renzheng Huan1,2

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This study presents a novel nanoprodrug (RMM@GEM NPs) for glioblastoma (GBM) treatment. The RMM@GEM NPs enhance drug delivery across the blood-brain barrier, activating anti-tumor immunity and improving therapeutic outcomes.

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Area of Science:

  • Oncology
  • Nanomedicine
  • Immunotherapy

Background:

  • Glioblastoma (GBM) is a highly aggressive brain tumor with a poor prognosis.
  • Gemcitabine (GEM) shows anticancer activity but faces challenges in crossing the blood-brain barrier (BBB).
  • The tumor microenvironment in GBM is often immunosuppressive, hindering effective treatment.

Purpose of the Study:

  • To develop a dual-responsive biomimetic nanoprodrug for enhanced GBM treatment.
  • To improve BBB penetration and targeted delivery of gemcitabine.
  • To activate anti-tumor immune responses and overcome tumor immunosuppression.

Main Methods:

  • Fabrication of RMM@GEM NPs using glioblastoma cell membranes and targeting peptide RAP.
  • Evaluation of BBB penetration and tumor accumulation of RMM@GEM NPs.
  • Assessment of GEM release triggered by tumor microenvironment stimuli (ROS, acidity).
  • Analysis of STING pathway activation and immune cell modulation (PD-L1, T-cell exhaustion).

Main Results:

  • RMM@GEM NPs demonstrated efficient BBB penetration and selective accumulation in glioma lesions.
  • Dual-responsive drug release activated STING signaling pathways (p-STING, p-TBK1, p-IRF3, p-NF-κB).
  • Cholesterol depletion suppressed PD-L1 expression and alleviated T-cell exhaustion, enhancing anti-tumor immunity.

Conclusions:

  • RMM@GEM NPs represent a promising strategy for enhancing immune responses in "cold" GBM tumors.
  • This approach offers a potential avenue for efficient and safe immunotherapy in GBM treatment.
  • The dual-responsive biomimetic nanoprodrug design holds potential for overcoming therapeutic challenges in brain tumors.