Charge-switchable nanoparticles enhance Cancer immunotherapy based on mitochondrial dynamic regulation and immunogenic cell death induction
| Autor: | Jingwen Liu, Ming Zhao, Ji Li, Dawei Chen, Moxi Xu, Haiyang Hu, Hongrui Ji, Siwen Wu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Macrophage polarization Pharmaceutical Science Immunogenic Cell Death 02 engineering and technology CD8-Positive T-Lymphocytes Mitochondrial Dynamics 03 medical and health sciences Immune system Cancer immunotherapy Cell Line Tumor Neoplasms Tumor Microenvironment medicine Humans Prospective Studies 030304 developmental biology 0303 health sciences Tumor microenvironment Chemistry technology industry and agriculture 021001 nanoscience & nanotechnology mitochondrial fusion Cancer cell Cancer research Nanoparticles Immunogenic cell death Mitochondrial fission Immunotherapy 0210 nano-technology |
| Zdroj: | Journal of Controlled Release. 335:320-332 |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2021.05.036 |
| Popis: | Cancer immunotherapy has emerged as a promising option for various malignant tumors therapy. Unfortunately, the existence of an immunosuppressive tumor microenvironment (ITM) and the absence of an effective delivery strategy limit its further application. To reverse the ITM and exploit a favorable delivery system for cancer immunotherapy, twin-like charge-switchable nanoparticles (shMFN1-NPs + DOX-NPs, termed as MIX-NPs) were developed to selectively target tumor-associated macrophages (TAMs) and cancer cells, respectively. The shMFN1-NPs (150 nm) and DOX-NPs (160 nm) both had uniform spherical-shaped structures and showed favorable tumor tissue accumulation. Based on the pH-responsive core-shell separation, the nanoparticles obtained an excellent balance between the circulation time and cellular uptake. Mitochondrial dynamics are involved in macrophage polarization by regulating a novel signaling network, involving the modulation from fusion (M2-TAMs) to mitochondrial fission (M1-TAMs). M2-TAMs targeting nanoparticles shMFN1-NPs were fabricated to deliver shMFN1 for repolarization of TAMs from the M2 to M1 phenotype by inhibiting mitochondrial fusion. Moreover, DOX-NPs effectively triggered the immunogenic cell death (ICD) of cancer cells, and the succeeding maturation of dendritic cells (DCs) promoted the infiltration and activation of CD8+ T cells. MIX-NPs displayed the strongest antitumor efficacy (TIR = 83%) in the subcutaneous 4T1 tumor model. MIX-NPs suppressed the myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs) to further remodel the ITM. Taken together, our developed drug delivery strategy reversed the ITM and activated the antitumor immune response, providing a profound prospective treatment strategy in cancer immunotherapy. |
| Databáze: | OpenAIRE |
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