AI-Assisted Engineering of Glycyrrhizic Acid/Simvastatin Nanocrystals for Multifunctional Treatment of Bacterial Osteomyelitis.

Bacterial osteomyelitis remains a formidable challenge in clinic because existing monotherapies fail to block inevitable infection, uncontrolled inflammation, and impaired bone regeneration ‌concurrently. Here, we present an AI-assisted strategy that integrates antibacterial, anti-inflammatory, and pro-osteogenic activities into a single nanocrystal. Through machine learning‑assisted screening from FDA-approved active pharmaceutical ingredients (API), we identified glycyrrhizic acid and simvastatin as a multifunctional combination capable of self-assembling into uniform nanocrystals (SGNCs) with ultrahigh drug loading. SGNCs effectively neutralize reactive oxygen species, suppress M1 macrophage polarization, promote bactericidal effects, and reverse infection-impaired osteogenic differentiation. Mechanistically, RNA sequencing analysis further reveals that the beneficial effects of SGNCs are associated with the inhibition of inflammatory response via cytokine-cytokine receptor interaction pathway and the activation of bone regeneration program via the Wnt signaling pathway. As a consequence, SGNCs eradicate bacterial burden and restore bone microarchitecture with excellent biocompatibility in a rat osteomyelitis model. Our insights highlight an AI-assisted strategy that creates a mechanism-targeting nanomedicine solely from APIs for the efficient treatment of bacterial osteomyelitis, which currently requires multimodal management.