Release mechanism of micrometer-scale particles from transient networks with well-controlled structures

Abstract Practical applications of viral- and cell-based therapeutics require precise targeted delivery to minimize off-target effects. Conventional hydrogel-based drug delivery carriers may undergo a sol‒gel phase transition upon in vivo degradation, leading to a burst release of encapsulated substances. Transient-network materials have been proposed to overcome this challenge. However, the relationship between the network structure and release mechanisms remains unclear, mainly due to the lack of control over structural heterogeneity in typical transient networks. This study aimed to elucidate the mechanism underlying the release of micrometer-scale particles from transient networks using a systematically controlled model system composed of tetra-armed polyethylene glycol (Tetra-PEG slime). The system features a well-defined structure with uniform strand lengths and consistent functionalities. Our results demonstrate that particle release is driven by the dissolution of the matrix and that the release barrier depends on the surrounding network topology. This release behavior is primarily determined by network connectivity and is independent of the polymer concentration and strand length. These insights advance our understanding of the sustainable release of microparticles from transient networks and provide broadly applicable guidelines for the development of effective drug delivery systems.