Near-Infrared Light-Responsive Nanosystems with Controlled l-Quebrachitol Release and Photothermal Effect for Synergistic Bone Defect Regeneration

Recent breakthroughs emphasize the growing potential of natural plant extracts in advancing bone regeneration, with l-quebrachitol (LQ) standing out as a promising multifunctional agent. LQ, primarily found in plants from the Sapindaceae, Apocynaceae, and Elaeagnaceae families, has garnered attention for its unique therapeutic properties. In this study, we first utilized the PharmMapper platform to systematically identify pharmacological targets associated with bone formation and angiogenesis for LQ. We then conducted a series of experimental investigations to uncover the underlying signaling pathways, revealing the mechanistic basis for LQ's action. In order to address the limitations such as short biological half-lives and rapid in vivo degradation, we further integrated LQ into advanced drug delivery systems to enhance its bioavailability and therapeutic potential. Zeolitic imidazolate framework-8 (ZIF-8), a type of metal-organic framework, has a highly porous structure and marked surface area, making it an ideal candidate for drug delivery. We engineered a novel nanocomposite (ZIF-8-pTA-LQ) by surface-modifying ZIF-8 with poly-tannic acid (pTA) and encapsulating LQ within its pore structure. This nanocomposite not only enabled controlled release of LQ but also exhibited mild photothermal properties, rapidly heating to ~45 °C within 4 min under 1.2 W/cm² NIR irradiation and stabilizing below 50 °C within 10 min. The nanosystem facilitated the subsequent activation of the PI3K/Akt signaling pathway, resulting in exceptional performance in regenerating bone defects. This innovative nanoparticle platform, combining controlled drug release with photothermal therapy, presents a novel and highly effective approach to bone tissue repair, offering a promising new avenue for regenerative medicine.