Polyanhydride‐Based Microparticles for Programmable Pulsatile Release of Diphtheria Toxoid (DT) for Single‐Injection Self‐Boosting Vaccines

Abstract Vaccination remains a critical tool in preventing infectious diseases, yet its effectiveness is undermined by under‐immunization, particularly for vaccines requiring multiple doses that patients fail to complete. To address this challenge, the development of single‐injection platforms delivering self‐boosting vaccines has gained significant attention. Despite some advances, translating these platforms into clinical applications has been limited. In this study, a novel polyanhydride‐based polymeric delivery platform is introduced, designed for single‐injection self‐boosting vaccines, replacing multiple doses. Over 20 polyanhydride polymers are synthesized and screened, ultimately down selecting to 6 for in vitro studies, and 2 for in vivo studies. Using diphtheria toxoid (DT) as a model antigen, programmed pulsatile release with a narrow window is demonstrated, ideal for self‐boosting immunization. The platform effectively protects the pH‐sensitive antigen before release, achieving recovery rate of 39.7% to 89.7%. The system's tunability is further enhanced by machine learning algorithms, which accurately predict release profiles, confirmed through experimental validation. In vivo studies in a mouse model reveals that the platform induces DT‐specific antibody responses comparable to those generated by traditional multi‐dose regimens. Collectively, these findings highlight the potential of this platform to deliver various vaccines, offering a potentially promising solution to the global challenge of under‐immunization.