Macrophage membrane-reversibly camouflaged nanotherapeutics accelerate fracture healing by fostering MSCs recruitment and osteogenic differentiation.

The fracture healing outcome is largely dependent on the quantities as well as osteogenic differentiation capacities of mesenchymal stem cells (MSCs) at the lesion site. Herein, macrophage membrane (MM)-reversibly cloaked nanocomplexes (NCs) are engineered for the lesion-targeted and hierarchical co-delivery of short stromal derived factor-1α peptide (sSDF-1α) and Ckip-1 small interfering RNA (Ckip-1 siRNA, siCkip-1) to promote bone repair by concurrently fostering recruitment and osteogenic differentiation of endogenous MSCs. To construct the NCs, a membrane-penetrating α-helical polypeptide first assembles with siCkip-1, and the cationic NCs are sequentially coated with catalase and an outer shell of sSDF-1α-anchored MM. Due to MM-assisted inflammation homing, intravenously injected NCs could efficiently accumulate at the fractured femur, where catalase decomposes the local hydrogen peroxide to generate oxygen bubbles that drives the shedding of sSDF-1α-anchored MM in the extracellular compartment. The exposed, cationic inner core thus enables robust trans-membrane delivery into MSCs to induce Ckip-1 silencing. Consequently, sSDF-1α-guided MSCs recruitment cooperates with siCkip-1-mediated osteogenic differentiation to facilitate bone formation and accelerate bone fracture healing. This study provides an enlightened strategy for the hierarchical co-delivery of macromolecular drugs into different cellular compartments, and it also renders a promising modality for the management of fracture healing.

Macrophage Membrane-Reversibly Cloaked Nanotherapeutics for the Anti-Inflammatory and Antioxidant Treatment of Rheumatoid Arthritis.

During rheumatoid arthritis (RA) development, over-produced proinflammatory cytokines represented by tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) represented by H2 O2 form a self-promoted cycle to exacerbate the synovial inflammation and tissue damage. Herein, biomimetic nanocomplexes (NCs) reversibly cloaked with macrophage membrane (RM) are developed for effective RA management via dual scavenging of TNF-α and ROS. To construct the NCs, membrane-penetrating, helical polypeptide first condenses TNF-α siRNA (siTNF-α) and forms the cationic inner core, which further adsorbs catalase (CAT) via electrostatic interaction followed by surface coating with RM. The membrane-coated NCs enable prolonged blood circulation and active joint accumulation after systemic administration in Zymosan A-induced arthritis mice. In the oxidative microenvironment of joints, CAT degrades H2 O2 to produce O2 bubbles, which shed off the outer membrane layer to expose the positively charged inner core, thus facilitating effective intracellular delivery into macrophages. siRNA-mediated TNF-α silencing and CAT-mediated H2 O2 scavenging then cooperate to inhibit inflammation and alleviate oxidative stress, remodeling the osteomicroenvironment and fostering tissue repair. This study provides an enlightened strategy to resolve the blood circulation/cell internalization dilemma of cell membrane-coated nanosystems, and it renders a promising modality for RA treatment.

Correlation and reliability of cervical sagittal alignment parameters between plain radiographs and multipositional MRI images.

STUDY DESIGN: A retrospective study. OBJECTIVES: To assess the validity and reliability of cervical sagittal alignment parameters from multipositional magnetic resonance imaging (MRI) and dynamic cervical radiography. SETTING: Hospital in Suzhou, China. METHODS: Patients who underwent both multipositional MRI and dynamic plain radiography of the cervical spine within a 2-week interval between January 2013 and October 2021 were retrospectively enrolled in this study. The C2-7 angle, C2-7 cervical sagittal vertical axis (C2-7 SVA), T1 slope (T1S), cervical tilt, cranial tilt, and K-line tilt were measured in three different positions (neutral, flexion, and extension) with multipositional MRI and dynamic radiography. Inter- and intraobserver reliabilities were assessed by intraclass correlation coefficients (ICCs). Pearson correlation coefficients were used for statistical analyses. RESULTS: A total of 65 (30 males and 35 females) patients with a mean age of 53.4 years (range 23-69 years) were retrospectively enrolled in this study. Significant positive correlations were noted regarding all parameters between the plain radiographs and multipositional MRI images. Inter- and intraobserver reliabilities were excellent for all cervical sagittal alignment parameters measured in the two imaging modalities. All cervical sagittal parameters had significant positive correlations with those from multipositional MRI in all three positions (p < 0.05). Pearson correlation coefficients demonstrated moderate and strong correlations between the two examinations. CONCLUSIONS: Cervical sagittal alignment parameters measured on multipositional MRI could reliably substitute for those measured on plain radiographs. Multipositional MRI is a valuable, radiation-free alternative for diagnostic evaluation in degenerative cervical diseases.

Cytokine-scavenging nanodecoys reconstruct osteoclast/osteoblast balance toward the treatment of postmenopausal osteoporosis.

Imbalance between osteoblasts and osteoclasts accounts for the incidence and deterioration of postmenopausal osteoporosis. Abnormally elevated RANKL and TNF-α levels after menopause promote osteoclast formation and inhibit osteoblast differentiation, respectively. Here, nanodecoys capable of scavenging RANKL and TNF-α were developed from preosteoclast (RAW 264.7 cell) membrane­coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles, which inhibited osteoporosis and maintained bone integrity. The nanodecoys effectively escaped from macrophage capture and enabled prolonged blood circulation after systemic administration. The abundant RANK and TNF-α receptor (TNF-αR) on the cell membranes effectively neutralized RANKL and TNF-α to prevent osteoclastogenesis and promote osteoblastogenesis, respectively, thus reversing the progression of osteoporosis in the ovariectomized (OVX) mouse model. These biomimetic nanodecoys provide an effective strategy for reconstructing the osteoclast/osteoblast balance and hold great potentials for the clinical management of postmenopausal osteoporosis.

LncRNA MM2P-induced, exosome-mediated transfer of Sox9 from monocyte-derived cells modulates primary chondrocytes.

Monocyte-derived cells were shown to promote cartilage repair in osteoarthritis. The role of the long non-coding RNA (lncRNA) MM2P in this function of monocyte-derived cells remained unexplored. Treatment of RAW264.7 murine macrophages and mouse bone marrow-derived macrophages with IL-4 or IL-13 upregulated MM2P expression, upstream of STAT3 and STAT6 phosphorylation. Specifically, MM2P blocked SHP2-mediated dephosphorylation of STAT3 at Try705 and interacted with the RNA-binding protein FUS. In turn, p-STAT3 increased the Sox9 gene expression. These cells released Sox9 mRNA and protein-containing exosomes, as demonstrated by a transmission electron microscope, nanoparticle tracking analysis, and detection of typical surface markers. Their culture supernatant promoted the differentiation of mouse primary chondrocytes, i.e., upregulated the expression of Col1a2 and Acan genes and promoted the secretion of extracellular matrix components proteoglycan and type II collagen. These effects were mediated by Sox9 mRNA and protein delivered to chondrocytes by exosomes. Together, ex vivo treatment of monocyte-derived cells with IL-4 or IL-13 promoted chondrocyte differentiation and functions through exosome-mediated delivery of Sox9 mRNA and protein.

Correlation Between Dural Sac Size in Dynamic Magnetic Resonance Imaging and Clinical Symptoms in Patients with Lumbar Spinal Stenosis.

OBJECTIVE: To assess the dynamic change of the dural sac size in patients with lumbar spinal stenosis (LSS) from supine to standing position and their correlation with clinical symptoms. METHODS: A total of 110 patients with LSS were prospectively enrolled to undergo both supine (0°) and standing (78°) magnetic resonance imaging (MRI). Dural sac cross-sectional area (DCSA) and dural sac anteroposterior diameter (DAPD) at the most constricted spinal level in supine and standing MRI were measured and compared. Clinical symptoms were assessed by duration of disease, claudication distance, visual analog scale (VAS) score of leg pain, and Chinese Oswestry Disability Index score of low back pain. The correlation between the parameters and clinical symptoms was analyzed by Pearson correlation coefficient (r). RESULTS: Mean minimum DCSA and DAPD in the standing position were significantly smaller (both P < 0.01) than in the supine position. DCSA and DAPD in standing MRI and their changes had better correlation with the intermittent claudication distance and VAS score of leg pain than in the supine position. A more than 15 mm2 reduction of DSCA was observed in patients with shorter claudication distance and more severe VAS score of leg pain (both P < 0.01). CONCLUSIONS: Dural sac size on MRI was reduced significantly from supine to standing position. Standing MRI and the changes of DCSA significantly correlated with claudication distance and VAS score of leg pain in patients with LSS. Therefore, standing MRI provides more radiologic information correlating with clinical symptoms in patients with LSS than supine MRI.