Capturing Transient Intermediate Assembly States Enables Hierarchical Core-Shell Microassemblies with Spatiotemporal...

Coordinated delivery of therapeutics with distinct physicochemical properties remains a fundamental challenge in drug design. This difficulty often stems from incompatible assembly kinetics, in which mismatched assembly behaviors among components lead to disordered structures and hinder functional integration. Here, we report a cascade assembly strategy to construct core-shell microassemblies (MTX@HPTD) by capturing transient intermediate states, enabling sequential structural organization and functional integration for spatiotemporal drug release. Upon solvent exchange, methotrexate (MTX) and phenylboronic acid-modified hyaluronic acid (HP) coassemble, thereby allowing the capture of an intermediate in which a dense MTX-rich core forms while the surrounding HP shell remains accessible for subsequent integration. This enables covalent anchoring of ROS-scavenging TEMPO-doped polydopamine nanoparticles (TPDA) into the evolving shell of the intermediate assembly via dynamic covalent bonding. The resulting core-shell microassemblies, featuring an MTX-rich reservoir stabilized by a functionalized HP-rich shell that entraps the TPDA payload, exhibit spatially segregated compartments, enabling diffusion-controlled release of MTX and stimuli-responsive release of TPDA. Moreover, by utilizing changes in the size of microassemblies during release, this system addresses the size-dependent trade-off between retention and uptake. In a psoriasis model, microneedle-mediated delivery achieves coordinated therapy, suppressing ferroptosis, necroptosis, and HMGB1 signaling, thereby mitigating disease severity. This work establishes the temporal capture of transient states as a promising strategy for constructing hierarchical materials for spatiotemporal release.