Beyond PEGylation: Polysarcosine as a Next-Generation Stealth Polymer for Long-Acting Depot Drug Delivery

Introduction: In long-acting injectable (LAI) depot systems, polysarcosine (PSar), a hydrophilic, biodegradable polypeptoid, is emerging as a clinically significant alternative to polyethylene glycol (PEG). In contrast to PEG, which has drawbacks such as tissue buildup and immunogenicity, PSar offers improved biocompatibility, enzymatic degradability, and a lower risk of hypersensitivity. Methods: The literature from 2015 to 2025 was systematically reviewed using Web of Science, PubMed, and Scopus. The synthesis methods, physicochemical characteristics, depot performance, and therapeutic uses of PSar-based nanocarriers were examined in these studies. The pharmacokinetic, immunological, and translational results were evaluated by extracting comparative data with PEGylated systems. Results: PSar-based nanocarriers reduced complement activation, protein adsorption, and macrophage uptake, resulting in enhanced stealth behavior. PSar-containing depot formulations extended drug release from weeks to months, decreased burst release, and achieved pH-neutral breakdown. Comparative research revealed that PSar-modified lipid nanoparticles for mRNA delivery had longer circulation times and a lower risk of hypersensitivity. Preclinical studies in disorders of the central nervous system, endocrinology, and cancer showed improved hormone release profiles and extended therapeutic efficacy. Discussion: The modular chemistry of PSar enables the development of smart depot systems, such as theranostic and stimuli-responsive platforms, while meeting new regulatory requirements for biodegradable excipients. Beyond PEG substitution, its translational benefits provide a basis for tailored and adaptable nanomedicine. Conclusion: A revolutionary platform for depot technologies, polysarcosine combines therapeutic accuracy, biodegradability, and safety. PSar is positioned as a clinically promising polymer for next-generation long-acting injectable treatments thanks to this review's unique synthesis of comparative pharmacological evidence and translational insights.