• MSCs therapy holds promise for immunomodulation and tissue repair but is limited by poor infusion, survival, and engraftment.
• Preconditioning MSCs with natural small molecule compounds (NSMs) enhances their therapeutic efficacy for organ injury repair.
• NSMs regulate MSCs to improve repair in vital organs including heart, liver, kidney, and pancreas.
• Future clinical translation requires addressing challenges in MSC preconditioning and standardization.