Mechanistically, co-administration of VitD3 and E2 elicits enhanced pro-osteogenic effects by virtue of VitD3-mediated Vitamin D Receptor (VDR) upregulation and amplified E2-induced estrogen receptor (ER) expression, which collectively drive robust activation of the PI3K/AKT/mTOR signaling cascade.This bone-specific nanoplatform offers a promising and safer strategy for osteoporosis therapy beyond conventional HRT. The gene discussed is AKT1; the disease is osteoporosis.