Programming Mn(II) coordination in self-assembling peptides amplifies mtDNA-driven STING signaling for potent...

Area of Science:

• Biotechnology
• Nanomedicine
• Immunotherapy

Background:

• The cGAS-STING pathway is a key target for cancer immunotherapy, but its activation is limited by insufficient cytosolic DNA.
• Developing strategies to enhance cytosolic DNA availability is crucial for effective STING pathway activation.

Purpose of the Study:

• To develop a bioinspired metallopeptide nanoassembly (RKLAHE-Mn) for targeted cancer immunotherapy.
• To investigate the mechanism of RKLAHE-Mn in activating the cGAS-STING pathway and its therapeutic potential.

Main Methods:

• Self-assembly of RKLAHE-Mn through Mn(II) and peptide coordination.
• Assessment of ROS generation, mitochondrial membrane potential, and mtDNA release.
• Evaluation of STING pathway activation in immune cells and tumor models.
• In vivo studies in murine breast cancer models assessing tumor microenvironment remodeling and therapeutic efficacy.

Main Results:

• RKLAHE-Mn self-assembles into uniform nanoassemblies via Mn-His/Glu coordination.
• Internalization of RKLAHE-Mn induces ROS burst, mitochondrial dysfunction, and mtDNA release, amplifying STING signaling.
• RKLAHE-Mn promotes dendritic cell maturation and enhances T cell infiltration in tumors.
• Combined therapy with RKLAHE-Mn and anti-PD-L1 significantly improves anti-tumor efficacy.

Conclusions:

• Metal-coordination-guided peptide self-assembly offers a versatile platform for developing targeted nanotherapeutics.
• RKLAHE-Mn effectively converts ionic cofactors into immunostimulatory agents, enhancing cancer immunotherapy.
• This approach shows promise for overcoming limitations in STING pathway activation for cancer treatment.