Rational Design of Zwitterionic Nanosystems to Overcome Biological Barriers for Drug Delivery by Various Administration Routes

The drug delivery nanosystems (DDNS) have demonstrated excellent potential in numerous drug modifications reliant on the physical and chemical properties. However, the main challenge in the clinical application transformation of DDNS lies in the biological barriers between the administration site and the target site, which hinders efficient drug transport. The polyethylene glycol (PEG)-modified stealth strategies that have been clinically approved have also been questioned due to inherent defects such as accelerated blood clearance and specific immune responses. As an alternative to PEG, zwitterion polymers with characteristics including forming a strong hydration layer, extremely low immunogenicity, and ultra-delayed blood circulation time have stood out in the surface modification of DDNS for various administration routes. This review introduces the biological barriers faced by drugs in various administration routes, elaborates on the advantages of the inherent properties of zwitterions in overcoming these barriers, and focuses on the latest progress in how zwitterions can flexibly modify DDNS to achieve superior delivery efficiency and efficacy in various administration routes. Finally, the rational design of zwitterion-modified DDNS for future disease treatment is envisioned. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.