Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss

The clinical role and underlying mechanisms of valproic acid(VPA)on bone homeostasis remain controversial.Herein,we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density(BMD)in both patients and mice.This effect was attributed to VPA-induced elevation in osteoclast formation and activity.Through RNA-sequencing,we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro,and further,a marked upregulation of mature miR-6359(miR-6359)in vivo was demonstrated using quantitative real-time PCR(qRT-PCR)and miR-6359 fluorescent in situ hybridization(miR-6359-FISH).Specifically,the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils,T lymphocytes,monocytes and bone marrow-derived mesenchymal stem cells(BMSCs)following VPA stimulation,which influenced osteoclast differentiation and bone-resorptive activity.Additionally,VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species(ROS)production by silencing the SIRT3 protein expression,followed by activation of the MAPK signaling pathway,which enhanced osteoclast formation and activity,thereby accelerating bone loss.Currently,there are no medications that can effectively treat VPA-induced bone loss.Therefore,we constructed engineered small extracellular vesicles(E-sEVs)targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif(CGGGAGC)in the 3’-end of the anti-miR-6359 sequence.We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss,but not on ovariectomy(OVX)and glucocorticoid-induced osteoporotic models,deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

Immunomodulatory Nanosystems:Advanced Delivery Tools for Treating Chronic Wounds

The increasingly aging society led to a rise in the prevalence of chronic wounds(CWs),posing a significant burden to public health on a global scale.One of the key features of CWs is the presence of a maladjusted immune microenvironment characterized by persistent and excessive(hyper)inflammation.A variety of immunomodulatory therapies have been proposed to address this condition.Yet,to date,current delivery systems for immunomodulatory therapy remain inadequate and lack efficiency.This highlights the need for new therapeutic delivery systems,such as nanosystems,to manage the pathological inflammatory imbalance and,ultimately,improve the treatment outcomes of CWs.While a plethora of immunomodulatory nanosystems modifying the immune microenvironment of CWs have shown promising therapeutic effects,the literature on the intersection of immunomodulatory nanosystems and CWs remains relatively scarce.Therefore,this review aims to provide a comprehensive overview of the pathogenesis and characteristics of the immune microenvironment in CWs,discuss important advancements in our understanding of CW healing,and delineate the versatility and applicability of immunomodulatory nanosystems-based therapies in the therapeutic management of CWs.In addition,we herein also shed light on the main challenges and future perspectives in this rapidly evolving research field.

State of the art in enzymatic debridement

Surgical treatment of deep partial thickness to full thickness burn wounds by knife has been the undisputed standard of care and was one key point in surgical burn medicine for decades. Recently, it gets more and more challenged by Bromelain-based enzymatic burn wound debridement (ED) as technique for non-surgical, selective eschar removal. Although the literature on ED is increasing constantly it cannot comprise the rapid progress that is made in clinical application of ED. To outline the current state of art in ED, recent literature as well as clinical experience is summarized and the main steps in clinical application including indications, wound preparation, application of the enzyme, wound bed assessment and further treatment after ED are discussed. Initial indications and limitations in application of ED could be gradually extended to increase versatility of ED as tool in burn surgery. Several randomized controlled trials compared ED to standard of care (SOC). They could show significant shorter time to complete burn wound debridement and wound closure, reduced need for surgery, reduced blood loss, reduced area of burns that needed surgical excision and need for autograft as well as an improved scar quality. Further research is necessary to justify an extensive use of ED as tool for burn eschar removal. Especially a robust comparison to surgical burn wound excision by knife as SOC is required to facilitate evidence-based burn surgery.