Sclerostin-targeted delivery of PCSK9 siRNA reverses osteoporosis in OVX mice.

The role of PCSK9 in bone metabolism has recently emerged as a critical area of research. This study identifies a significant upregulation of PCSK9, approximately 1.2-fold in ovariectomized (OVX) mice serum, approximately 3-fold in OVX mice bone marrow stem cells, which correlates strongly with decreased bone mineral density, implicating PCSK9 in estrogen deficiency-induced bone loss. Genetic knockout of PCSK9 was found to ameliorate osteoporosis by improving bone microarchitecture, increasing trabecular bone volume fraction (BV/TV) by 50%, enhancing bone formation (serum PINP increased by 30%), and bone resorption (serum β-CTX increased by 10%), confirming its dual regulatory function. Based on these findings, we engineered a bone-targeted exosome delivery system by surface functionalizing exosomes with an anti-sclerostin (anti-SCL) fragment. This novel system facilitated efficient bone-specific enrichment (fluorescence intensity in bone increased by 60%) and the successful delivery of siPCSK9, resulting in potent silencing of bone marrow PCSK9 expression. In OVX osteoporotic mice, this targeted intervention markedly attenuated bone loss. A 2-fold increase in bone mass was observed relative to the untreated OVX group. Our work not only elucidates a pivotal role of PCSK9 in osteoporosis pathogenesis but also provides a compelling proof-of-concept for exosome-based precision therapy, offering substantial potential for clinical translation.