Selective CDK9 knockdown sensitizes TRAIL response by suppression of antiapoptotic factors and NF-kappaB pathway.

The aberrantly up-regulated CDK9 can be targeted for cancer therapy. The CDK inhibitor dinaciclib (Dina) has been found to drastically sensitizes cancer response to TRAIL-expressing extracellular vesicle (EV-T). However, the low selectivity of Dina has limited its application for cancer. We propose that CDK9-targeted siRNA (siCDK9) may be a good alternative to Dina. The siCDK9 molecules were encapsulated into EV-Ts to prepare a complexed nanodrug (siEV-T). It was shown to efficiently suppress CDK9 expression and overcome TRAIL resistance to induce strikingly augmented apoptosis in lung cancer both in vitro and in vivo, with a mechanism related to suppression of both anti-apoptotic factors and nuclear factor-kappa B pathway. Therefore, siEV-T potentially constitutes a novel, highly effective and safe therapy for cancers.

3WJ RNA Nanoparticles-Aptamer Functionalized Exosomes From M2 Macrophages Target BMSCs to Promote the Healing of Bone Fractures.

Up to now, impaired bone regeneration severely affects the healing of bone fractures, thus bringing tremendous suffering to patients. As a vital mediator between inflammatory response and bone regeneration, M2 macrophage-derived exosomes (M2-Exos) attenuate inflammation and promote tissue repair. However, due to a lack of specific targeting property, M2-Exos will be rapidly eliminated after systematic administration, thus compromising their effectiveness in promoting bone regeneration. To solve this hurdle, we initially harvested and characterized the pro-osteogenic properties of M2-Exos. A bone marrow mesenchymal stem cell (BMSC)-specific aptamer was synthesized and 3-way junction (3WJ) RNA nanoparticles were applied to conjugate the BMSC-specific aptamer and M2-Exos. In vitro assays revealed that M2-Exos bore the representative features of exosomes and significantly promoted the proliferation, migration, and osteogenic differentiation of BMSCs. 3WJ RNA nanoparticles-aptamer functionalized M2-Exos (3WJ-BMSCapt/M2-Exos) maintained the original physical characteristics of M2-Exos, but bore a high specific binding ability to BMSCs. Furthermore, when being systemically administered in the mice model with femoral bone fractures, these functionalized M2-Exos mainly accumulated at the bone fracture site with a slow release of exosomal cargo, thereby significantly accelerating the healing processes compared with the M2-Exos group. Our study indicated that the 3WJ-BMSCapt/M2-Exos with BMSCs targeting ability and controlled release would be a promising strategy to treat bone fractures.