Semi-randomized zwitterionic peptides: a breakthrough in drug delivery.

Abstract

Nanoparticle drug delivery systems (NP DDS) have transformed therapeutic delivery by improving drug stability, extending circulation time, and enabling targeted biodistribution. However, clinical translation remains limited by protein corona formation, immune recognition, and accelerated blood clearance following repeated administration. Poly(ethylene glycol) (PEG) has been the gold-standard antifouling material for decades, but emerging anti-PEG immune responses have driven the search for alternative stealth technologies. Zwitterionic peptides (ZIPs) have emerged as a promising class of antifouling materials because they combine the hydration-mediated stealth properties of zwitterionic polymers with the molecular precision and programmability of peptide synthesis. Here, ZIP applications in drug delivery were reviewed using the Web of Science database from 2014-2026, focusing on reducing and controlling the protein corona, recent advances in ZIP-based drug delivery, and the potential of high-throughput screening platforms and machine learning-guided ZIP design. Recent studies suggest that biological interactions of ZIP-functionalized NPs are governed primarily by charge motifs rather than precise sequences, creating new opportunities for material design. This observation motivates developing semi-randomized ZIPs (srZIPs) that preserve charge organization while introducing sequence diversity. By maintaining key physicochemical and biological properties while diversifying composition, srZIPs may reduce immune recognition without sacrificing antifouling function.

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