Engineering Supramolecular Nanomedicine for Targeted Near Infrared-triggered Mitochondrial Dysfunction to Potentiate Cisplatin for Efficient Chemophototherapy.

Combinatorial cancer therapies based on nanomedicine have emerged as a promising strategy to achieve potentiated treatment efficiency. Herein, cisplatin (CDDP) prodrug (Pt-CD) and a mitochondria-targeted near-infrared (NIR) photosensitizer IR780 were combined to construct a multifunctional nanomedicine IR780@Pt NPs through a supramolecular self-assembly strategy. Targeted mitochondrial dysfunction of cancer cells was sufficiently induced under NIR laser irradiation through both photothermal and photodynamic effects, inhibiting the overactive mitochondrial energy pathways of cancer cells. The mitochondrial dysfunction significantly attenuated the crosstalk between mitochondria and nucleus via the cellular ATP energy chain, leading to obvious down-regulation of the key proteins of the nucleotide excision repair (NER) pathway. Thereby, the chemotherapeutic effect of CDDP could be significantly potentiated because of reduced DNA lesion repair capacity by ERCC1-XPF nuclease system. Moreover, IR780@Pt NPs exhibited excellent NIR fluorescence and photoacoustic (PA) imaging capacity for in vivo imaging-guided NIR laser treatment. Ultimately, the IR780@Pt NPs mediated combinatorial chemophototherapy achieved potentiated anticancer efficacy against cancer cells in vitro and tumor inhibition performance in vivo. Overall, this study highlighted the significance of nanomedicine mediated targeted induction of mitochondrial dysfunction to potentiate chemotherapy for efficient combinatorial cancer therapy.

Local delivery of mutant CCL2 protein-reduced orthopaedic implant wear particle-induced osteolysis and inflammation in vivo.

Total joint replacement (TJR) has been widely used as a standard treatment for late-stage arthritis. One challenge for long-term efficacy of TJR is the generation of ultra-high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle-induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle-induced osteolysis and the effects of 7ND treatment were evaluated using micro-CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle-induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle-induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs.

Zinc finger protein 64 promotes Toll-like receptor-triggered proinflammatory and type I interferon production in macrophages by enhancing p65 subunit activation.

The molecular mechanisms that fine-tune the Toll-like receptor (TLR)-triggered innate immune response need further investigation. As an important transcription factor, zinc finger proteins (ZFPs) play important roles in many cell functions, including development, differentiation, tumorigenesis, and functions of the immune system. However, the role of ZFP members in the innate immune responses remains unclear. Here we showed that the expression of C2H2-type ZFP, ZFP64, was significantly up-regulated in macrophages upon stimulation with TLR ligands, including LPS, CpG oligodeoxynucleotides, or poly(I:C). ZFP64 overexpression promoted TLR-triggered TNF-α, IL-6, and IFN-ß production in macrophages. Coincidently, knockdown of ZFP64 expression significantly inhibited the production of the above cytokines. However, activation of MAPK and IRF3 was not responsible for the ZFP64-mediated promotion of cytokine production. Interestingly, ZFP64 significantly up-regulated TLR-induced NF-κB activation. ZFP64 could bind to the promoter of the TNF-α, IL-6, and IFN-ß genes in macrophages only after TLR ligation. Furthermore, ZFP64 associated with the NF-κB p65 subunit upon LPS stimulation, and TLR-ligated macrophages showed a lower level of p65 recruitment to the TNF-α, IL-6, and IFN-ß gene promoter in the absence of ZFP64. The data identify ZFP64 as a downstream positive regulator of TLR-initiated innate immune responses by associating with the NF-κB p65 subunit, enhancing p65 recruitment to the target gene promoters and increasing p65 activation and, thus, leading to the promotion of TLR-triggered proinflammatory cytokine and type I interferon production. Our findings add mechanistic insight into the efficient activation of the TLR innate response against invading pathogens.