Engineered plant extracellular vesicles for autoimmune diseases therapy

Autoimmune diseases(AID)encompass a diverse array of conditions characterized by immune system dysregulation,resulting in aberrant responses of B cells and T cells against the body’s own healthy tissues.Plant extracellular vesicles(PEVs)are nanoscale particles enclosed by phospholipid bilayers,secreted by plant cells,which facilitate intercellular communication by transporting various bioactive molecules.Due to their nanoscale structure,safety,abundant sources,low immunogenicity,high yield,biocompatibility,and effective targeting of the colon and liver,PEVs are regarded as a promising platform for the treatment of AID.This review provides a comprehensive summary of PEV biogenesis,physicochemical and biological properties,internalization mechanisms,isolation methods,and their applications in various diseases,with a specific focus on their potential roles in AID.Additionally,we propose engineering approaches and administration methods for PEVs.Finally,we present an overview of the advantages and challenges associated with utilizing PEVs for the treatment of AID.By gaining a comprehensive understanding of PEVs,we anticipate the development of innovative therapeutic strategies for AID.Natural and engineered PEVs hold substantial promise as a valuable resource for innovative technologies in AID treatment.

Harnessing exosomes for targeted therapy:strategy and application

Exosomes,nanoscopic extracellular vesicles produced by cells,are pivotal in mediating intracellular communication by transporting nucleic acids,proteins,lipids,and other bioactive molecules,thereby influencing physiological and pathological states.Their endogenous origin and inherent diversity confer distinct advantages over synthetic vehicles like liposomes and nanoparticles in diagnostic and therapeutic applications.Despite their potential,the clinical utility of exosomes is hampered by challenges such as limited storage stability,yield,purity,and targeting efficiency.This review focuses on exosomes as targeted therapeutic agents,examining their biogenesis,classification,isolation,and characterisation,while also addressing the current limitations in yield,purity,and targeting.We delve into the literature to propose optimisation strategies that can enhance their therapeutic efficacy and accelerate the translation of exosome-based therapies into clinical practice.

Light-activated nanoclusters with tunable ROS for wound infection treatment

Infected wounds pose a significant clinical challenge due to bacterial resistance, recurrent infections, and impaired healing. Reactive oxygen species (ROS)-based strategies have shown promise in eradicating bacterial infections. However, the excess ROS in the infection site after treatments may cause irreversible damage to healthy tissues. To address this issue, we developed bovine serum albumin-iridium oxide nanoclusters (BSA-IrOx NCs) which enable photo-regulated ROS generation and scavenging using near infrared (NIR) laser. Upon NIR laser irradiation, BSA-IrOx NCs exhibit enhanced photodynamic therapy, destroying biofilms and killing bacteria. When the NIR laser is off, the nanoclusters' antioxidant enzyme-like activities prevent inflammation and repair damaged tissue through ROS clearance. Transcriptomic and metabolomic analyses revealed that BSA-IrOx NCs inhibit bacterial nitric oxide synthase, blocking bacterial growth and biofilm formation. Furthermore, the nanoclusters repair impaired skin by strengthening cell junctions and reducing mitochondrial damage in a fibroblast model. In vivo studies using rat infected wound models confirmed the efficacy of BSA-IrOx NCs. This study presents a promising strategy for treating biofilm-induced infected wounds by regulating the ROS microenvironment, addressing the challenges associated with current ROS-based antibacterial approaches.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis

Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(MMP13).Herein,we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable,cyanine 5(Cy5)-containing PEG,black hole quencher-3(BHQ3),and cRGD ligands and loaded with siRNA silencing MMP13(siM13),namely ERMs@siM13.ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell,causing cRGD exposure.Accordingly,the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surfaceαvβ3 integrin,increasing intracellular siM13 delivery for on-demand MMP13 downregulation.Meanwhile,the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle,precisely reflecting the diseased cartilage state.In particular,the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity,enabling the physicians to adjust the therapeutic regimen.Finally,in the murine PTOA model,ERMs@siM13 could diagnose the early-stage PTOA,perform timely interventions,and monitor the OA progression level during treatment through a real-time detection of MMP13.Therefore,ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer:a clinical and translational study

p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,DNMT1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage IV TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Generation artificial intelligence(GenAI)and Biomaterials Translational:steering innovation without misdirection

In the dynamic landscape of generative artificial intelligence(GenAI),recent developments,such as the artificial research organisation OpenAI’s introduction of the text-to-video generation tool Sora,have again catapulted GenAI into the limelight.Thus reigniting discussions on the swift march towards an era of future controlled usage of artificial general intelligence(AGI).Concurrently,in the realm of scientific research,the use of GenAI tools like DALL·E to generate inaccurate scientific illustrations for publication and the skepticism surrounding findings published in Nature from the AI-driven automated laboratory,A-Lab,have sparked widespread scientific controversy1.

Magnesium-based biomaterials for coordinated tissue repair:A comprehensive overview of design strategies,advantages,and challenges

Magnesium-based biomaterials(MBMs)are one of the most promising materials for tissue engineering due to their unique mechanical properties and excellent functional properties.This review describes the development,advantages,and challenges of MBMs for biomedical applications,especially for tissue repair and regeneration.The history of the use of MBMs from the beginning of the 20th century is traced,and the transformative advances in contemporary applications of MBMs in areas such as orthopedics and cardiovascular surgery are emphasized.The review also provides insight into the signaling pathways affected by MBMs,such as the PI3K/Akt and RANKL/RANK/OPG pathways,which are critical for osteogenesis and angiogenesis.The review advocates that future research should focus on optimizing alloy compositions,surface modification and exploring innovative technologies such as 3D printing to improve the efficacy of MBMs in complex tissue repair.The potential of MBMs to tissue engineering and regenerative medicine is significant,urging further exploration and interdisciplinary collaboration to maximize their therapeutic effects.

Smart Hydrogels for Bone Reconstruction via Modulating the Microenvironment

Rapid and effective repair of injured or diseased bone defects remains a major challenge due to shortages of implants.Smart hydrogels that respond to internal and external stimuli to achieve therapeutic actions in a spatially and temporally controlled manner have recently attracted much attention for bone therapy and regeneration.These hydrogels can be modified by introducing responsive moieties or embedding nanoparticles to increase their capacity for bone repair.Under specific stimuli,smart hydrogels can achieve variable,programmable,and controllable changes on demand to modulate the microenvironment for promoting bone healing.In this review,we highlight the advantages of smart hydrogels and summarize their materials,gelation methods,and properties.Then,we overview the recent advances in developing hydrogels that respond to biochemical signals,electromagnetic energy,and physical stimuli,including single,dual,and multiple types of stimuli,to enable physiological and pathological bone repair by modulating the microenvironment.Then,we discuss the current challenges and future perspectives regarding the clinical translation of smart hydrogels.

Organoid extracellular vesicle-based therapeutic strategies for bone therapy

With the rapid development of population ageing,bone-related diseases seriously affecting the life of the elderly.Over the past few years,organoids,cell clusters with specific functions and structures that are self-induced from stem cells after three-dimensional culture in vitro,have been widely used for bone therapy.Moreover,organoid extracellular vesicles(OEVs)have emerging as promising cell-free nanocarriers due to their vigoroso physiological effects,significant biological functions,stable loading capacity,and great biocompatibility.In this review,we first provide a comprehensive overview of biogenesis,internalisation,isolation,and characterisation of OEVs.We then comprehensively highlight the differences between OEVs and traditional EVs.Subsequently,we present the applications of natural OEVs in disease treatment.We also summarise the engineering modifications of OEVs,including engineering parental cells and engineering OEVs after isolation.Moreover,we provide an outlook on the potential of natural and engineered OEVs in bone-related diseases.Finally,we critically discuss the advantages and challenges of OEVs in the treatment of bone diseases.We believe that a comprehensive discussion of OEVs will provide more innovative and efficient solutions for complex bone diseases.

Converging technologies in biomaterial translational research

In the realm of scientific innovation,the study of biomaterials emerges as a field of profound significance,bridging the gap between theoretical exploration and translational application.1 The essence of biomaterial research lies not only in understanding the intricate relationships between biological systems and materials but more importantly,in the translational potential these materials hold.2 The true value of this research unfolds in its application-from regenerative medicine to bioengineered solutions,where these materials become pivotal in addressing some of the most pressing clinical challenges.Meanwhile,the necessity for translating laboratory research into real-world applications has become increasingly urgent,as global ageing intensifies and public attention to health concerns grows.

Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor

Osteoarthritis(OA),a common degenerative disease,is characterized by high disability and imposes substantial economic impacts on individuals and society.Current clinical treatments remain inadequate for effectively managing OA.Organoids,miniature 3D tissue structures from directed differentiation of stem or progenitor cells,mimic native organ structures and functions.They are useful for drug testing and serve as active grafts for organ repair.However,organoid construction requires extracellular matrix-like 3D scaffolds for cellular growth.Hydrogel microspheres,with tunable physical and chemical properties,show promise in cartilage tissue engineering by replicating the natural microenvironment.Building on prior work on SF-DNA dual-network hydrogels for cartilage regeneration,we developed a novel RGD-SF-DNA hydrogel microsphere(RSD-MS)via a microfluidic system by integrating photopolymerization with self-assembly techniques and then modified with Pep-RGDfKA.The RSD-MSs exhibited uniform size,porous surface,and optimal swelling and degradation properties.In vitro studies demonstrated that RSD-MSs enhanced bone marrow mesenchymal stem cells(BMSCs)proliferation,adhesion,and chondrogenic differentiation.Transcriptomic analysis showed RSD-MSs induced chondrogenesis mainly through integrin-mediated adhesion pathways and glycosaminoglycan biosynthesis.Moreover,in vivo studies showed that seeding BMSCs onto RSD-MSs to create cartilage organoid precursors(COPs)significantly enhanced cartilage regeneration.In conclusion,RSD-MS was an ideal candidate for the construction and long-term cultivation of cartilage organoids,offering an innovative strategy and material choice for cartilage regeneration and tissue engineering.

AI-enabled organoids:Construction,analysis,and application

Organoids,miniature and simplified in vitro model systems that mimic the structure and function of organs,have attracted considerable interest due to their promising applications in disease modeling,drug screening,personalized medicine,and tissue engineering.Despite the substantial success in cultivating physiologically relevant organoids,challenges remain concerning the complexities of their assembly and the difficulties associated with data analysis.The advent of AI-Enabled Organoids,which interfaces with artificial intelligence(AI),holds the potential to revolutionize the field by offering novel insights and methodologies that can expedite the development and clinical application of organoids.This review succinctly delineates the fundamental concepts and mechanisms underlying AI-Enabled Organoids,summarizing the prospective applications on rapid screening of construction strategies,cost-effective extraction of multiscale image features,streamlined analysis of multi-omics data,and precise preclinical evaluation and application.We also explore the challenges and limitations of interfacing organoids with AI,and discuss the future direction of the field.Taken together,the AI-Enabled Organoids hold significant promise for advancing our understanding of organ development and disease progression,ultimately laying the groundwork for clinical application.

Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical-size bone defect repair

Segmental bone defects,stemming from trauma,infection,and tumors,pose formidable clinical challenges.Traditional bone repair materials,such as autologous and allogeneic bone grafts,grapple with limitations including source scarcity and immune rejection risks.The advent of nucleic acid nanotechnology,particularly the use of DNA hydrogels in tissue engineering,presents a promising solution,attributed to their biocompatibility,biodegradability,and programmability.However,these hydrogels,typically hindered by high gelation temperatures(~46◦C)and high construction costs,limit cell encapsulation and broader application.Our research introduces a novel polymer-modified DNA hydrogel,developed using nucleic acid nanotechnology,which gels at a more biocompatible temperature of 37◦C and is cost-effective.This hydrogel then incorporates tetrahedral Framework Nucleic Acid(tFNA)to enhance osteogenic mineralization.Furthermore,considering the modifiability of tFNA,we modified its chains with Aptamer02(Apt02),an aptamer known to foster angiogenesis.This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells(BMSCs)and angiogenesis in human umbilical vein endothelial cells(HUVECs),with cell sequencing confirming their targeting efficacy,respectively.In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation.This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction,marking a significant advancement in tissue engineering and regenerative medicine.

EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway

Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer cells.Notably,elevated expression of EHMT2 had been validated in UM samples.Furthermore,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage.Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2.Its transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA activity.Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes.Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key molecules.In summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.

3-D bioprinted human-derived skin organoids accelerate full-thickness skin defects repair

The healing of large skin defects remains a significant challenge in clinical settings.The lack of epidermal sources,such as autologous skin grafting,limits full-thickness skin defect repair and leads to excessive scar formation.Skin organoids have the potential to generate a complete skin layer,supporting in-situ skin regeneration in the defect area.In this study,skin organoid spheres,created with human keratinocytes,fibroblasts,and endothelial cells,showed a specific structure with a stromal core surrounded by surface keratinocytes.We selected an appropriate bioink and innovatively combined an extrusion-based bioprinting technique with dual-photo source cross-linking technology to ensure the overall mechanical properties of the 3D bioprinted skin organoid.Moreover,the 3D bioprinted skin organoid was customized to match the size and shape of the wound site,facilitating convenient implantation.When applied to full-thickness skin defects in immunodeficient mice,the 3D bioprinted human-derived skin organoid significantly accelerated wound healing through in-situ regeneration,epithelialization,vascularization,and inhibition of excessive inflammation.The combination of skin organoid and 3D bioprinting technology can overcome the limitations of current skin substitutes,offering a novel treatment strategy to address large-area skin defects.

Engineering vascularised organoid-on-a-chip:strategies,advances and future perspectives

In recent years,advances in microfabrication technology and tissue engineering have propelled the development of a novel drug screening and disease modelling platform known as organoid-on-a-chip.This platform integrates organoids and organ-on-a-chip technologies,emerging as a promising approach for in vitro modelling of human organ physiology.Organoid-on-a-chip devices leverage microfluidic systems to simulate the physiological microenvironment of specific organs,offering a more dynamic and flexible setting that can mimic a more comprehensive human biological context.However,the lack of functional vasculature has remained a significant challenge in this technology.Vascularisation is crucial for the long-term culture and in vitro modelling of organoids,holding important implications for drug development and personalised medical approaches.This review provides an overview of research progress in developing vascularised organoid-on-a-chip models,addressing methods for in vitro vascularisation and advancements in vascularised organoids.The aim is to serve as a reference for future endeavors in constructing fully functional vascularised organoid-on-a-chip platforms.

Skeletal organoids

The skeletal system,composed of bones,muscles,joints,ligaments,and tendons,serves as the foundation for maintaining human posture,mobility,and overall biomechanical functionality.However,with ageing,chronic overuse,and acute injuries,conditions such as osteoarthritis,intervertebral disc degeneration,muscle atrophy,and ligament or tendon tears have become increasingly prevalent and pose serious clinical challenges.These disorders not only result in pain,functional loss,and a marked reduction in patients’quality of life but also impose substantial social and economic burdens.Current treatment modalities,including surgical intervention,pharmacotherapy,and physical rehabilitation,often do not effectively restore the functionality of damaged tissues and are associated with high recurrence rates and long-term complications,highlighting significant limitations in their efficacy.Thus,there is a strong demand to develop novel and more effective therapeutic and reparative strategies.Organoid technology,as a three-dimensional micro-tissue model,can replicate the structural and functional properties of native tissues in vitro,providing a novel platform for in-depth studies of disease mechanisms,optimisation of drug screening,and promotion of tissue regeneration.In recent years,substantial advancements have been made in the research of bone,muscle,and joint organoids,demonstrating their broad application potential in personalised and regenerative medicine.Nonetheless,a comprehensive review of current research on skeletal organoids is still lacking.Therefore,this article aims to present an overview of the definition and technological foundation of organoids,systematically summarise the progress in the construction and application of skeletal organoids,and explore future opportunities and challenges in this field,offering valuable insights and references for researchers.

Organoids:the future of disease modelling and therapeutics

In the rapidly advancing field of biomedical research,organoid technology has been a groundbreaking development.Organoids-three-dimensional structures derived from stem cells that replicate key structural and functional features of human tissues-have transformed approaches to disease modelling,1 drug discovery,2 and regenerative medicine.3 With the ability to mimic human organs more accurately than traditional cell cultures or animal models,organoids offer tremendous potential for advancing precision medicine and personalised therapies.

Artificial intelligence-enabled studies on organoid and organoid extracellular vesicles

In the field of medical research,studies of organoids and organoid extracellular vesicles(OEVs)are leading a revolutionary change.1 Organoids are simplified,miniaturised versions of organs that simulate the microenvironment of human tissues,and have broad applications in disease modelling,drug development,and regenerative medicine.Extracellular vesicles(EVs)are tiny vesicles secreted from various cells,containing proteins,lipids,RNA,and other biomolecules.

Broad-spectrum rescue compounds for structural p53 mutations: perspective on ‘Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site’

Precision medicine targeting gene mutations holds the promise of changing the landscape of cancer care and prognosis,but currently approved drugs in this category are efficacious in only a very small percentage of all cancer patients(Tannock and Hickman,2016).TP53,encoding the tumor suppressor and transcription factor p53,is the most frequently mutated gene in human cancers(Joerger and Fersht,2016;Sabapathy and Lane,2018;Levine,2019).Pharmacologically rescuing mutant p53 by restoring wild-type function could therefore potentially be widely applicable in cancer treatment and is considered to be a holy grail of cancer research(Joerger and Fersht,2010).Indeed,at least 17 compounds that can rescue mutant p53 variants were reported by 2018(Sabapathy and Lane,2018).Unfortunately,p53 mutations still remain therapeutically nonactionable due to challenges such as heterogeneous mechanisms of inactivation by different mutations and the absence of obvious targetable drug-binding pockets(except Y220C mutant).In a recent publication(Chen et al.,2021),we reported the identification of small-molecule compounds that rescue a broad class of p53 mutations.Notably,these include arsenic trioxide(ATO),which is used to treat acute promyelocytic leukemia(de Théet al.,2017).The study differentiates itself from previous reports in:(i)rescuing mutant p53 at striking levels when benchmarked against previously reported rescue compounds;(ii)providing a structural mechanism,wherein the arsenic atom binds to a cryptic allosteric site connecting the loop–sheet–helix(LSH)motif with theβ-sandwich skeleton to increase the thermostability of mutant p53;(iii)offering a largely defined spectrum of applicable p53 mutations—the structural mutations that compromise the wild-type structure of p53 and collectively account for more than half of all clinically relevant p53 alterations.