Abstract:Microspheres have emerged as a pivotal platform for micron‐scale drug delivery, yet their utility has been greatly hindered by limitations in biodegradability, drug loading efficiency, and release kinetics, underscoring the urgent need for a next‐generation microsphere platform that integrates high performance, scalability, and multifunctionality. Leveraging host–guest recognition, a series of macrocycle‐incorporated polymers is synthesized and engineered a new class of supramolecular microspheres, which feature precisely tunable components, including host molecules, guest cargoes, and polymer components, as well as customizable morphologies, while enabling cost‐effective, large‐scale production. Following systematic validation of the host–guest recognition between β‐cyclodextrin (β‐CD) and lanreotide, we developed supramolecular microspheres (LAN@S‐CPMs) that achieve a drug loading capacity and release duration approximately twice that of conventional microspheres, effectively curbing the disease progression of acromegaly. Beyond sustained release, porous supramolecular microspheres (S‐P[5]PMs‐p) fabricated from the pillar[5]arene (P[5])‐incorporated polymer exhibit exceptional efficiency in spermine adsorption, while mineralized supramolecular microspheres (SORA@S‐CPMs‐p@CaCO3) loaded with sorafeinib (SORA) are successfully employed in embolization therapy, achieving more complete vascular occlusion compared to non‐mineralized microspheres. The modular design of supramolecular microspheres and facile scalability in production offer a transformative platform to overcome the multifaceted challenges currently faced by microsphere‐based delivery systems.