Rationally Designed Zwitterionic Peptides Improve siRNA Delivery of Cationic Diblock Copolymer-Based Nanoparticle...

Nanoparticle drug delivery systems (NP DDS) have proven to be tremendously impactful for delivering therapeutic agents in cancer treatments, vaccinations, gene therapy, diagnostics, and enabled new agents such as RNA therapeutics. However, the exposure of NP DDS to biological milieus leads to the rapid adsorption of proteins and other molecules, forming a proteinaceous corona that obscures NP surface characteristics and controls the biological interactions of the NP DDS. This corona often potentiates phagocytic uptake, hindering the efficacy of targeting groups, and reducing NP drug delivery efficacy. Surface modifications to reduce protein adsorption can overcome these deleterious effects. Still, the repertoire of modifications is limited to poly(ethylene glycol) (PEG)and synthetic zwitterionic polymers. However, these anti-fouling strategies lack tunability, have off-target immunological effects, and suffer from targeting-limited steric hindrance, altogether motivating the development of alternative approaches. Peptides can uniquely form many zwitterions and have shown promise in reducing and controlling NP protein coronas as a function of peptide sequence. However, the impact of ZIPs on the drug delivery properties of polymeric NPs has not been explored. In this work, diverse zwitterionic peptides (ZIPs) predicted computationally to reduce protein adsorption by assessing peptide-peptide β-strand interaction energies were conjugated to pH-responsive cationic NPs. The resulting ZIP-NP conjugates exhibited up to 88% reduced protein adsorption versus unfunctionalized NP, resulting in a range of siRNA-mediated gene knockdown, outcomes that correlate with interaction energies. These data suggest that interaction energy is a promising design parameter for ZIPs. ZIP-NP also exhibited sequence-dependent variations in cellular uptake and circulation half-life, indicating ZIP-NPs are suitable for tuning and improving NP drug delivery characteristics.