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

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.