Biomimetic nanodecoys reconstruct the osteoclast/osteoblast balance to treat postmenopausal osteoporosis.

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.

Dysregulated inflammation and failure in resolution account for the incidence and deterioration of rheumatoid arthritis (RA). IL‐4 and miR‐21 possess complementary functions in inhibiting inflammation and fostering resolution. Thus, inflammation‐instructed nanocomplexes (NCs) are herein developed to mediate hierarchical co‐delivery of miR‐21 and IL‐4 to orchestrate the osteoimmune microenvironment against RA. The NCs comprise a cationic inner core assembled from the membrane‐penetrating, helical polypeptide (PG) and miR‐21, an outer layer based on the acid‐responsive, charge reversal polymer (PLL‐CA), and surface‐adsorbed IL‐4. The negatively charged NCs enable prolonged blood circulation after systemic administration, and thus passively accumulate in the inflamed joint. In the slightly acidic microenvironment of inflamed synovium, PLL‐CA transforms from negative to positive, which sheds off to liberate IL‐4 extracellularly and facilitate the intracellular delivery of the PG/miR‐21 core into macrophages. Thus, the anti‐inflammatory miR‐21 cooperates with the proresolving IL‐4 to attenuate inflammation via NF‐κB inhibition, promote macrophage polarization to M2a/M2c phenotypes, propel resolution, and promote tissue repair against Zymosan A‐induced arthritis. This study provides an effective strategy toward the programmed delivery of drug/gene cargoes at different extracellular/intracellular locations, and the combined mechanism of anti‐inflammation and proresolution renders insights into the treatment of inflammatory diseases.

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During rheumatoid arthritis (RA) development, over‐produced proinflammatory cytokines represented by tumor necrosis factor‐α (TNF‐α) and reactive oxygen species (ROS) represented by H2O2 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 H2O2 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 H2O2 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.