Biomaterial-Driven Nanodrug Formulation for Enhanced Bone Regeneration in Osteoporosis

Nanoformulation-based drug delivery offers significant potential for achieving targeted and nontargeted delivery to bone and cartilage tissues by exploiting nanoscale properties such as high surface area, enhanced solubility, and improved cellular uptake. Self-nanoemulsifying drug delivery systems (SNEDDs), as advanced biomaterial-based nanocarriers, provide a promising platform to overcome the solubility and bioavailability limitations of poorly water-soluble drugs. In this study, low doses of Raloxifene (RX) and Cladrin (CD) were coloaded into SNEDDs, generating a stable nanosystem with an average particle size of <200 nm, optimized via the Box–Behnken design. RX-CD-SNEDDs exhibited ∼2-fold higher in vitro release and ∼3.91-fold higher cellular uptake compared to free-RX-CD, attributed to their nanoscale dimensions and biomaterial composition. In vitro studies revealed significantly enhanced ALP activity, reduced apoptosis, low hemolysis, and improved osteoblast proliferation. Pharmacokinetic analysis demonstrated a marked increase in oral bioavailability, while histopathological examination confirmed the nanoformulation’s biocompatibility. In vivo, RX-CD-SNEDDs improved bone mineral density (BMD), trabecular microarchitecture, and bone quality in ovariectomized (OVX) rats, with superior outcomes at L5 vertebrae compared to tibia and femur. The nanoformulation also normalized bone-turnover markers (increased PINP, decreased CTX), improved body composition, and supported uterine health recovery. Micro-CT analysis further confirmed significant restoration of bone strength. Collectively, the nanoscale design of RX-CD-SNEDDs enabled enhanced pharmacological performance, demonstrating strong potential for treating postmenopausal osteoporosis.