Alendronate-functionalized ZIF-8 nanoplatform for targeted delivery of SHH siRNA and docetaxel to treat prostate cancer bone metastasis.

Sonic hedgehog (SHH) signaling plays a crucial role in prostate carcinogenesis, especially in the context of bone metastasis. SHH can activate the SHH signaling network in the bone metastasis microenvironment by promoting osteoclast maturation and osteoblast calcium deposition, both of which accelerate bone metastasis progression. We here designed a multifunctional ZIF-8 lipid nanoparticle drug delivery system to enhance therapeutic effectiveness. The system was loaded with SHH siRNA at the core and docetaxel (DTXL) in the outer layers of the nanoparticle (NP). The NP surface was modified with the alendronate-conjugated DOPE-PEG polymer to specifically target bone metastasis. The SHH siRNA and DTXL-loaded NPs effectively inhibited the in vitro proliferation and colony formation of PC-3 cells, induced their G2/M phase cell cycle arrest, and promoted apoptosis. Moreover, the conditioned medium from the PC-3 and MC3T3-E1 co-culture triggered osteoclast and osteoblast differentiation. In the mouse model of prostate cancer bone metastasis, these ZIF-8 NPs selectively accumulated at the bone metastasis sites, effectively suppressing prostate cancer growth. Additionally, these drug-loaded ZIF-8 NPs exhibited good biocompatibility, making them a promising therapeutic approach for prostate cancer bone metastasis.