BMSC-targeting aptamer conjugation enhances bone delivery of a rice bran peptide to mitigate osteoporosis via eIF3L.

Osteoporosis is frequently accompanied by a shift in the fate of bone marrow mesenchymal stromal cells (BMSCs) from osteogenesis toward adipogenesis, contributing to bone-fat imbalance and fragility fractures. Here, we evaluated a naturally occurring eight-amino acid rice bran-derived peptide, RBAP (KHNRGDEF), together with an aptamer-RBAP conjugate designed to improve bone accumulation via a previously identified BMSC-targeting nucleic acid aptamer. In ovariectomized mice, RBAP administered either preventively (early after ovariectomy) or therapeutically (after osteoporotic phenotypes had developed) preserved trabecular microarchitecture, improved mechanical properties, reduced marrow adiposity, and accelerated osteoporotic fracture healing. RBAP also conferred bone-protective effects in models of natural aging and disuse osteoporosis. In vitro, RBAP promoted osteogenic differentiation and suppressed adipogenic differentiation of primary BMSCs without detectably affecting osteoclastogenesis. Proteomic pull-down and functional screening identified eukaryotic translation initiation factor 3 subunit L (eIF3L) as a key RBAP-interacting protein, and genetic suppression of eIF3l attenuated RBAP-induced osteogenesis and blunted its bone protective capacity in vivo. Conjugation of RBAP to the BMSC-targeting aptamer increased BMSC uptake and bone tissue accumulation, thereby enhancing its pro-osteogenic and anti-osteoporotic effects at the same administered dose. Our study identifies RBAP as a bioactive peptide candidate for correcting bone-fat imbalance in osteoporosis and support aptamer conjugation as a modular strategy to improve bone delivery.