Engineering Metal-Organic-Framework-Based STING Nanoagonists for PROTAC-Enhanced Cancer Chemo-Metalloimmunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Chemo-metalloimmunotherapy shows promise but faces challenges like chemoresistance and immune escape due to PD-L1 upregulation.
• Developing integrated therapeutic strategies is crucial to enhance cancer treatment efficacy.

Purpose of the Study:

• To develop a multifunctional nanoplatform integrating chemotherapy, metalloimmunotherapy, and PROTAC-mediated epigenetic modulation for enhanced cancer treatment.
• To overcome chemoresistance and PD-L1-mediated immune evasion.

Main Methods:

• A manganese-based metal-organic framework nanoplatform (Mn-CDDP-dBET6@CM) was designed.
• The platform co-delivers manganese ions (Mn2+), cisplatin (CDDP), and a BRD4-targeting PROTAC (dBET6).
• Tumor cell membranes were used for coating to achieve homologous targeting and immune evasion.

Main Results:

• The nanoplatform effectively activates the STING pathway, induces DNA damage, and promotes mitochondrial DNA release.
• It suppresses PD-L1 expression, induces cellular senescence, and enhances innate and adaptive immune responses.
• In vitro and in vivo studies showed significant tumor growth inhibition, increased dendritic cell maturation, and elevated cytotoxic T cell infiltration.

Conclusions:

• The multifunctional nanoplatform demonstrates potent anti-tumor efficacy by overcoming chemoresistance and immunosuppression.
• This approach offers a versatile strategy for next-generation chemo-metalloimmunotherapy.
• The integrated system shows potential for advanced cancer treatment modalities.