Cationic polymers have found increased use in biomedicine as endosomolytic drug and gene delivery systems, engineered tissues, and antimicrobial coatings, among other applications. Despite the promise of these materials, many fail clinical trials due to unpredictable systemic toxicity and/or immunogenic responses. High positive charge density, tendency to form nanoparticles, and ability to form charge-based interactions with proteins cause such polymers can disrupt cellular and organelle membranes and/or activate innate immune receptors such as the NLRP3 inflammasome, yet the precise biophysical interactions underpinning these responses have failed to be screened in a comprehensive manner. In this work, we seek to understand the physicochemical properties of polymers which result in a toxic or immunogenic response. 107 polymers varied in charge density, hydrophobicity, and molecular weight using RAFT polymerization in a process chemistry approach and screened for their toxicity and ability to activate the NLRP3 inflammasome. Based on the results of this screen, we use confocal microscopy to identify how physicochemical properties modulate polymer-cell interactions. We show that positive charge and hydrophobicity synergize to induce cell membrane disruption or lysosomal rupture and inflammasome activation. Finally, by developing a “Trojan Horse” approach to screen immunotoxic positive charge, we demonstrate the efficacy of our immunogenic polymer adjuvants for use in vaccination.

High throughput screening of cationic polymers reveals distinct modes of cellular interactions and immunomodulation for biomedical applications

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ACS Fall 2022

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