Senescence-Targeted and NAD+-Dependent SIRT1-Activated Nanoplatform to Counteract Stem Cell Senescence for Promoting Aged Bone Regeneration.

Age-related bone defects are a leading cause of disability and mortality in elderly individuals, and targeted therapy to delay the senescence of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a promising strategy to rejuvenate bone regeneration in aged scenarios. More specifically, activating the nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) pathway is demonstrated to effectively counteract MSC senescence and thus promote osteogenesis. Herein, based on an inventively identified senescent MSC-specific surface marker Kremen1, a senescence-targeted and NAD+ dependent SIRT1 activated nanoplatform is fabricated with a dual delivery of resveratrol (RSV) (SIRT1 promoter) and nicotinamide riboside (NR, NAD+ precursor). This targeting nanoplatform exhibits a strong affinity for senescent MSCs through conjugation with anti-Kremen1 antibodies and enables specifically responsive release of NR and RSV in lysosomes via senescence-associated ß-galactosidase-stimulated enzymatic hydrolysis of the hydrophilic chain. Furthermore, this nanoplatform performs well in promoting aged bone formation both in vitro and in vivo by boosting NAD+, activating SIRT1, and delaying MSC senescence. For the first time, a novel senescent MSC-specific surface marker is identified and aged bone repair is rejuvenated by delaying senescence of MSCs using an active targeting platform. This discovery opens up new insights for nanotherapeutics aimed at age-related diseases.

Rejuvenating Aged Bone Repair through Multihierarchy Reactive Oxygen Species-Regulated Hydrogel.

Aging exacerbates the dysfunction of tissue regeneration at multiple levels and gradually diminishes individual's capacity to withstand stress, damage, and disease. The excessive accumulation of reactive oxygen species (ROS) is considered a hallmark feature of senescent stem cells, which causes oxidative stress, deteriorates the host microenvironment, and eventually becomes a critical obstacle for aged bone defect repair. Till now, the strategies cannot synchronously and thoroughly regulate intracellular and extracellular ROS in senescent cells. Herein, a multihierarchy ROS scavenging system for aged bone regeneration is developed by fabricating an injectable PEGylated poly(glycerol sebacate) (PEGS-NH2 )/poly(γ-glutamic acid) (γ-PGA) hydrogel containing rapamycin-loaded poly(diselenide-carbonate) nanomicelles (PSeR). This PSeR hydrogel exhibits highly sensitive ROS responsiveness to the local aged microenvironment and dynamically releases drug-loaded nanomicelles to scavenge the intracellular ROS accumulated in senescent bone mesenchymal stem cells. The PSeR hydrogel effectively tunes the antioxidant function and delays senescence of bone mesenchymal stem cells by safeguarding DNA replication in an oxidative environment, thereby promoting the self-renewal ability and enhancing the osteogenic capacity for aged bone repair in vitro and in vivo. Thus, this multihierarchy ROS-regulated hydrogel provides a new strategy for treating degenerative diseases.

Eukaryotic translation initiation factor 4E family member nCBP facilitates the accumulation of TGB-encoding viruses by recognizing the viral coat protein in potato and tobacco.

Due to their limited coding capacity, plant viruses have to depend on various host factors for successful infection of the host. Loss of function of these host factors will result in recessively inherited resistance, and therefore, these host factors are also described as susceptibility genes or recessive resistance genes. Most of the identified recessive resistance genes are members of the eukaryotic translation initiation factors 4E family (eIF4E) and its isoforms. Recently, an eIF4E-type gene, novel cap-binding protein (nCBP), was reported to be associated with the infection of several viruses encoding triple gene block proteins (TGBps) in Arabidopsis. Here, we, for the first time, report that the knockdown of nCBP in potato (StnCBP) compromises the accumulation of potato virus S (PVS) but not that of potato virus M (PVM) and potato virus X (PVX), which are three potato viruses encoding TGBps. Further assays demonstrated that StnCBP interacts with the coat proteins (CPs) of PVS and PVM but not with that of PVX, and substitution of PVS CP in the PVS infectious clone by PVM CP recovered the virus infection in StnCBP-silenced transgenic plants, suggesting that the recognition of PVS CP is crucial for StnCBP-mediated recessive resistance to PVS. Moreover, the knockdown of nCBP in Nicotiana benthamiana (NbnCBP) by virus-induced gene silencing suppressed PVX accumulation but not PVM, while NbnCBP interacted with the CPs of both PVX and PVM. Our results indicate that the nCBP orthologues in potato and tobacco have conserved function as in Arabidopsis in terms of recessive resistance against TGB-encoding viruses, and the interaction between nCBP and the CP of TGB-encoding virus is necessary but not sufficient to determine the function of nCBP as a susceptibility gene.