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 itseffectiveness is undermined by under-immunization, particularly for vaccinesrequiring multiple doses that patients fail to complete. To address this chal-lenge, the development of single-injection platforms delivering self-boostingvaccines has gained significant attention. Despite some advances, translatingthese platforms into clinical applications has been limited. In this study, anovel polyanhydride-based polymeric delivery platform is introduced, designedfor single-injection self-boosting vaccines, replacing multiple doses. Over20 polyanhydride polymers are synthesized and screened, ultimately downselecting to 6 for in vitro studies, and 2 for in vivo studies. Using diphtheriatoxoid (DT) as a model antigen, programmed pulsatile release with a narrowwindow is demonstrated, ideal for self-boosting immunization. The platformeffectively protects the pH-sensitive antigen before release, achieving recoveryrate of 39.7% to 89.7%. The system’s tunability is further enhanced by machinelearning algorithms, which accurately predict release profiles, confirmedthrough experimental validation. In vivo studies in a mouse model revealsthat the platform induces DT-specific antibody responses comparable to thosegenerated by traditional multi-dose regimens. Collectively, these findingshighlight the potential of this platform to deliver various vaccines, offering apotentially promising solution to the global challenge of under-immunization.