Suppression of osteoclast multinucleation via a posttranscriptional regulation–based spatiotemporally selective delivery system

Abstract

Redundancy of multinucleated mature osteoclasts, which results from the excessive fusion of mononucleated preosteoclasts (pOCs), leads to osteolytic diseases such as osteoporosis. Unfortunately, the currently available clinical drugs completely inhibit osteoclasts, thus interfering with normal physiological bone turnover. pOC-specific regulation may be more suitable for maintaining bone homeostasis. Here, circBBS9, a previously unidentified circular RNA, was found to exert regulatory effects via the circBBS9/miR-423-3p/Traf6 axis in pOCs. To overcome the long-standing challenge of spatiotemporal RNA delivery to cells, we constructed biomimetic nanoparticles to achieve the pOC-specific targeted delivery of circBBS9. pOC membranes (POCMs) were extracted to camouflage cationic polymer for RNA interference with circBBS9 (POCM-NPs@siRNA/shRNA circBBS9 ). POCM-NPs endowed the nanocarriers with improved stability, accurate pOC targeting, fusogenic uptake, and reactive oxygen species–responsive release. In summary, our findings may provide an alternative strategy for multinucleated cell–related diseases that involves restriction of mononucleated cell multinucleation through a spatiotemporally selective delivery system.

Modulating osteoclasts with nanoparticles: A path for osteoporosis management?

“…These nanoparticles were able to block the multicleation of BMMs and their consequent nucleation in vitro and avoid bone loss in an OVX‐induced OP mouse model when intravenously administered every 3 days for 3 weeks. Moreover, the biodistribution studies show an exceptional accumulation in bone with no appreciable organ toxicity (Wang, Wang, et al, 2022).…”

Bioactives and Biomaterial Construction for Modulating Osteoclast Activities

“…Furthermore, innovative approaches include designing biomimetic OC delivery systems encapsulating specific RNA molecules, such as circBBS9, a circular RNA, via cationic polymer nanoparticles covered with pOC membranes. [ 136 ] These systems demonstrated a remarkable reduction in multinucleation in pOC, decreasing OC maturation in vitro. Moreover, they exhibited excellent biodistribution to bone in vivo without reported side effects in an osteoporosis mouse model.…”

“…Moreover, they exhibited excellent biodistribution to bone in vivo without reported side effects in an osteoporosis mouse model. [ 136 ]…”

Neutralization of Intracellular pH Homeostasis to Inhibit Osteoclasts Based on a Spatiotemporally Selective Delivery System

“…In our previous study, the precursor osteoclast membrane was used as a spatiotemporally targeted drug delivery system. As a carrier for drug delivery, the precursor osteoclast membrane can be used to recognize the precursor osteoclast through membrane fusion and enter osteoclasts to function in cells . Therefore, the precursor osteoclast membrane is a particularly suitable carrier for drug delivery.…”

“…As a carrier for drug delivery, the precursor osteoclast membrane can be used to recognize the precursor osteoclast through membrane fusion and enter osteoclasts to function in cells. 17 osteoclast membrane is a particularly suitable carrier for drug delivery. Na 2 HPO 4 is a weak alkaline substance that widely exists in the internal environment and cells.…”