2025 AIChE Annual Meeting

(31c) Next Generation Polymer Nanoparticles (PNPs) for Delivery of Encoded Biologics

Authors

John Fisher, Nanite
Nate Snell, Nanite
Suteja Patil, Nanite
Monoclonal antibodies (mAbs) have transformed modern drug discovery and development campaigns over the past decades, advancing treatments for cancer, autoimmune, and infectious diseases. These pharmaceutical products are twice as likely to succeed in clinical trials over small molecules but are notoriously expensive to biomanufacture, complicated to stabilize for long-lasting shelf life, and challenging to deliver directly as large proteins. Most mAb products also must be administered by intravenous (IV) infusion in specialized healthcare settings. One appealing solution to these issues involves vectorizing therapeutic mAbs into encoding DNA, injecting this non-integrating payload into muscle, and allowing patients’ bodies to produce their own endogenous proteins over time. Polymer nanoparticles (PNPs) can enable this genetic shortcut to controlled release of mAbs, as polymer-based carriers are well poised for DNA encoded biologics (DEb) over viral and non-viral lipid-based options. In this work, we present customized PNPs that deliver plasmid DNA (pDNA) encoding for PGT121, an anti-HIV antibody that is undergoing clinical trials for HIV treatment or cure. Our SAYERTM materials informatics platform leverages large computational datasets of 5000+ in-house experimental polymers to facilitate materials discovery and refinement via deep learning. After screening polymer candidates for PGT121, intramuscular delivery of resorbable PNPs in mice resulted in >1 μg/mL mAb production over 56 days post-injection. This therapeutically relevant window has not been achieved for any other delivery system to date. Furthermore, the pharmacokinetic profile was tunable by pDNA dose, PNP formulation conditions, and animal re-dosing, enabling machine learning techniques to further optimize delivery performance. Finally, we show that PNPs for DEb delivery is a universal approach to secrete model peptides and small proteins with wide implications in obesity/diabetes, osteomalacia, muscular dystrophy, and liver disease.