Macrophages Intracellularly Gelated With Bioactive Hydrogels for Synergistic Neutralization, Eradication, and Osteopromotion in Periodontitis Treatment

ABSTRACT Conventional periodontitis therapy is limited by the lack of an all‐in‐one material with the desired functions of toxin neutralization, pathogen eradication, and osteopromotion. Exploiting the innate capacity of macrophages to recognize and neutralize pathological stimuli, this study develops novel engineered macrophage‐based materials: phytate/Zn 2 + ‐loaded gelated macrophages (PZ‐GMs). These materials are fabricated at room temperature by polymerizing polycationic hydrogels and loading phytate/Zn 2 + into live macrophages, innovatively integrating the natural immune neutralization function of intact macrophage membranes with the bioactivity of intracellular hydrogels. PZ‐GMs are found to eradicate >99.99% of pathogens, remove >90% of bacterial toxins, and eliminate >80% of related inflammatory factors, while simultaneously promoting bone repair through in situ mineralization and osteoinduction. They can be further incorporated into a hydrogel designed for acid‐triggered release, ensuring targeted delivery to inflamed sites. In a murine periodontitis model, PZ‐GMs facilitate periodontal regeneration via a dual mechanism: transforming the pathological microenvironment induced by bacteria and toxins and fostering the remodeling of an osteogenic microenvironment. Furthermore, oral microbiome homeostasis is restored. Collectively, PZ‐GMs represent a promising all‐in‐one neutralization–eradication–osteopromotion material for highly efficient periodontitis therapy.