Tumor microenvironment-targeted PROTAC nanoparticle self-assembly broadly predicted by structural descriptors

  • Sci Adv. 2025 Dec 5;11(49):eadu2292. doi: 10.1126/sciadv.adu2292.
Kristen C Vogt  1  2  3 ,  Magdalini Panagiotakopoulou  1 ,  Mandana T Manzari Honu  1 ,  Ana Marie Perea  1 ,  Xiaoping Hu  4 ,  Xufen Yu  4 ,  Raashed Raziuddin  1  2 ,  Quincey LaPlant  5 ,  Stephen Ruiz  1  2 ,  G Praveen Raju  6 ,  Jian Jin  4 ,  David A Scheinberg  1  2  3 ,  Daniel A Heller  1  2  3
Affiliations
  • 1. Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2. Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
  • 3. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 5. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6. Departments of Neurosciences and Pediatrics, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
PMID: 41348877 DOI: 10.1126/sciadv.adu2292
Abstract

Proteolysis-targeting chimeras (PROTACs) are catalytic protein degraders with promising preclinical activity. The clinical translation of PROTACs has been limited by poor pharmacologic properties and toxicities, in part due to their "non-druglike" characteristics, including large molecular weights. We found that the vast majority of PROTACs can self-assemble into nanoparticles, yielding nanoparticle PROTACs (nanoPROTACs) with ultrahigh drug loadings. While PROTAC molecular features can be deleterious to their pharmacokinetic properties, we found that they can drive nanoencapsulation more efficiently than FDA-approved small-molecule drugs. Using structure-based prediction algorithms, we identified spatial autocorrelation molecular descriptors that defined nanoPROTAC formation with 96% sensitivity at 100% specificity. NanoPROTACs, targeted to the tumor microenvironment via P-selectin, led to significantly enhanced tumor drug uptake, target degradation, tumor growth inhibition, and overall survival in solid tumor xenografts. These findings offer a broad strategy to improve the pharmacologic properties and therapeutic index of PROTACs and potentially Other non-druglike experimental therapeutics.

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