Spatiotemporal application of small molecules in fracture healing

Skeletal injuries and disorders are major causes of physical disability worldwide, posing an intractable clinical challenge. Within the field of regenerative medicine, researchers are continuously developing new therapeutic strategies to promote bone regeneration. Small molecules, defined as bioactive compounds with a molecular weight of <1,000 Da, have emerged as promising agents capable of precisely regulating intracellular signaling pathways to enhance bone regeneration. Their cost-effectiveness, superior membrane permeability, and minimal immunogenicity have positioned them at the forefront of both fundamental research and clinical applications. In recent years, advancements in artificial intelligence have accelerated the development and screening of small-molecule drugs, broadening their potential therapeutic applications. Furthermore, innovations in dynamic drug delivery systems have advanced the concept of spatial precision, enabling the controlled release of drug doses over time and achieving the spatiotemporal application of small molecules. These systems release specific small molecules in a sequence, synchronizing therapeutic interventions with the dynamic process of bone healing. Spatiotemporal delivery strategies, which effectively replicate the complex and highly ordered processes of bone healing, have the potential to reduce drug side effects and enhance healing efficacy. However, clinical translation remains hindered by insufficient spatiotemporal control and limited pharmacokinetic precision, challenges that this review explores in depth. We systematically examine stage-specific molecular targets of signaling pathways and their corresponding small molecule modulators. In addition, we discuss current approaches to spatiotemporal delivery strategies, such as stimuli-responsive delivery systems. Finally, we explore the status of clinical applications, the challenges encountered, and potential solutions regarding the spatiotemporal release strategy. We hope this review will contribute to the development of future spatiotemporal delivery strategies, ultimately improving outcomes for patients with impaired fracture healing.