Targeted Delivery of PD-L1-Derived Phosphorylation-Mimicking Peptides by Engineered Biomimetic Nanovesicles to Enhance Osteosarcoma Treatment

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Osteosarcoma is a rare, aggressive bone cancer primarily affecting young individuals.
• Programmed cell death 1 ligand 1 (PD-L1), an immune checkpoint protein, is highly expressed in osteosarcoma.
• Emerging evidence suggests non-plasma membrane (NPM)-localized PD-L1 has roles beyond immune regulation in osteosarcoma.

Purpose of the Study:

• To identify intracellular binding partners of NPM-localized PD-L1 in osteosarcoma.
• To elucidate the mechanism by which NPM-localized PD-L1 promotes tumor growth.
• To develop a targeted therapeutic strategy based on these findings.

Main Methods:

• Mass spectrometry and RNA-sequencing were employed to identify PD-L1 binding partners.
• Biochemical assays were used to confirm interactions and signaling pathways.
• A novel drug delivery system (Peptide@cRGD-M) was engineered for targeted peptide delivery.

Main Results:

• NPM-localized PD-L1 was found to interact with Insulin-like growth factor binding protein-3 (IGFBP3).
• This interaction activates mTOR signaling, promoting osteosarcoma tumor growth.
• Phosphorylation of PD-L1 by PGK1 enhances the PD-L1/IGFBP3 interaction.
• The engineered Peptide@cRGD-M effectively delivered a PD-L1-derived peptide to osteosarcoma lesions, demonstrating therapeutic efficacy.

Conclusions:

• NPM-localized PD-L1 plays a critical role in osteosarcoma progression through interaction with IGFBP3 and mTOR activation.
• PD-L1 phosphorylation is a key regulatory step in this process.
• A targeted peptide-based therapy utilizing a red blood cell membrane vesicle shows promise for inhibiting osteosarcoma growth.