From Stealth to Shuttle: Zwitterionic Polymers as Transcytosis Enablers

Crossing biological barriers remains a significant challenge in drug delivery, severely limiting the efficacy of many therapeutics. Zwitterionic polymers, traditionally employed as antifouling stealth coatings, are now emerging as active enablers of barrier traversal through transcytosis. This Concept surveys transcytosis-capable zwitterionic polymer designs, synthesizes evidence for adsorptive- and receptor-mediated pathways, and maps them onto key biological barriers. We emphasize strategies, exemplified herein, that combine minimal nonspecific protein adsorption to prolong blood circulation with precisely tuned cell interactions sufficient to trigger transcytosis for deep tissue penetration. Furthermore, we outline current challenges in developing such polymers and highlight opportunities for data-driven material discovery. Together, these insights reposition zwitterionic polymers from passive shields to programmable shuttles with substantial translational potential.