Anti-Protein-Adsorption Nano-Proteolysis Targeting Chimeras as a Potent Platform for Efficient Programmed Cell Death...

Area of Science:

• Biotechnology
• Nanomedicine
• Immunotherapy

Background:

• Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 shows promise but faces limitations due to adaptive PD-L1 upregulation.
• Nanoparticle-based proteolysis targeting chimeras (PROTACs) offer direct PD-L1 degradation, but protein corona formation hinders their efficacy.
• Existing nano-PROTACs face challenges with nonspecific protein adsorption, limiting target engagement and therapeutic potential.

Purpose of the Study:

• To develop a corona-free nano-PROTACs platform (CF-nPTs) that overcomes protein corona barriers for enhanced PD-L1 degradation.
• To investigate the ability of CF-nPTs to resist protein adsorption and improve target engagement.
• To evaluate the therapeutic efficacy of CF-nPTs in preclinical cancer models.

Main Methods:

• Integration of DSPE-PCB, a zwitterionic antifouling amphiphile, into micellar nano-PROTACs to create a corona-free system.
• Comparative analysis of CF-nPTs against existing nano-PROTACs platforms (Au, liposomal, micellar) regarding protein adsorption.
• Assessment of PD-L1 and E3 ligase corecruitment, proteasome-mediated degradation, and lymph-node targeting.
• Evaluation of tumor regression, survival extension, and immune activation in subcutaneous melanoma and lymph-node-metastasis models.

Main Results:

• CF-nPTs effectively resisted nonspecific protein adsorption, maintaining an ultraclean surface in biological fluids.
• Enhanced corecruitment of PD-L1 and E3 ligase was observed, leading to highly efficient proteasome-mediated PD-L1 degradation.
• The corona-free architecture promoted robust lymph-node targeting, amplifying immunotherapeutic efficacy.
• CF-nPTs achieved pronounced tumor regression, extended survival, and strong immune activation in preclinical models.

Conclusions:

• Protein-corona resistance is a critical factor determining nano-PROTACs performance.
• CF-nPTs represent a promising platform for efficient target protein degradation and enhanced cancer immunotherapy.
• This study establishes a new strategy for overcoming a fundamental barrier in nano-PROTACs development.