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

Xiang Lu1,2,3, Shihui Song1, Furui Qiu1

  • 1School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China.

ACS Nano
|February 6, 2026
PubMed

Insights

A novel corona-free nano-PROTACs platform (CF-nPTs) effectively degrades PD-L1, enhancing cancer immunotherapy. This breakthrough overcomes protein corona barriers, leading to significant tumor regression and improved survival in preclinical models.

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.
Keywords:
PD-L1anti-protein coronaimmunotherapylymph node targetnano-PROTACs

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