Current approaches of nanomedicines in the market and various stage of clinical translation

Compared with traditional drug therapy,nanomedicines exhibit intriguing biological features to increase therapeutic efficiency,reduce toxicity and achieve targeting delivery.This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials,which manifests a diversified trend in carrier types,applied indications and mechanisms of action.From the perspective of indications,this article presents an overview of the applications of nanomedicines involving the prevention,diagnosis and treatment of various diseases,which include cancer,infections,blood disorders,cardiovascular diseases,immuno-associated diseases and nervous system diseases,etc.Moreover,the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.

Update on the research and development of magnesium-based biodegradable implants and their clinical translation in orthopaedics

Biodegradable magnesium(Mg)or its alloys are desirable materials for development into new-generation internal fixation devices or implants with high biocompatibility,adequate mechanical modulus,and osteopromotive properties,which may overcome some of the drawbacks of the existing permanent orthopaedic implants with regard to stress-shielding of bone and beam-hardening effects on radiographic images.This review summarises the current research status of Mg-based orthopaedic implants in animals and clinical trials.First,detailed information of animal studies including bone fracture repair and anterior cruciate ligament reconstruction with the use of Mg-based orthopaedic devices is introduced.Second,the repair mechanisms of the Mg-based orthopaedic implants are also reviewed.Afterwards,reports of recent clinical cases treated using Mg-based implants in orthopaedics are summarised.Finally,the challenges and the strategies of the use of Mg-based orthopaedic implants are discussed.Taken together,the collected efforts in basic research,translational work,and clinical applications of Mg-based orthopaedic implants over the last decades greatly contribute to the development of a new generation of biodegradable metals used for the design of innovative implants for better treatment of orthopaedic conditions in patients with challenging skeletal disorders or injuries.

Research and clinical translation of trilayer stent-graft of expanded polytetrafluoroethylene for interventional treatment of aortic dissection

The aortic dissection(AD)is a life-threatening disease.The transcatheter endovascular aortic repair(EVAR)affords a minimally invasive technique to save the lives of these critical patients,and an appropriate stent-graft gets to be the key medical device during an EVAR procedure.Herein,we report a trilayer stent-graft and corresponding delivery system used for the treatment of the AD disease.The stent-graft is made of nitinol stents with an asymmetric Z-wave design and two expanded polytetrafluoroethylene(ePTFE)membranes.Each of the inner and outer surfaces of the stent-graft was covered by an ePTFE membrane,and the two membranes were then sintered together.The biological studies of the sintered ePTFE membranes indicated that the stent-graft had excellent cytocompatibility and hemocompatibility in vitro.Both the stent-graft and the delivery system exhibited satisfactory mechanical properties and operability.The safety and efficacy of this stent-graft and the corresponding delivery system were demonstrated in vivo.In nine canine experiments,the blood vessels of the animals implanted with the stent-grafts were of good patency,and there were no thrombus and obvious stenosis by angiography after implantation for 6months.Furthermore,all of the nine clinical cases experienced successful implantation using the stent-graft and its postrelease delivery system,and the 1-year follow-ups indicated the preliminary safety and efficacy of the trilayer stent-graft with an asymmetric Z-wave design for interventional treatment.

Current trends and key considerations in the clinical translation of targeted fluorescent probes for intraoperative navigation

The rapid development of fluorescence imaging for intraoperative navigation has spurred further development of targeted fluorescent probes in the past decade.Only a few nontargeted dyes,including indocyanine green and methylene blue,are currently applied for fluorescence guided surgery in the clinic.While no targeted fluorescent probes have been approved for the clinic,a number of them have entered clinical trials.These probes have emission wavelengths in the visible and near infrared(NIR)-I(700-900 nm)range.Among them,activatable probes and nanoprobes have generated special interest.Compared with NIR-I fluorescent probes,NIR-II(1000-1700 nm)fluorescent probes exhibit better intravital performance in terms of increased penetration depths,reduced tissue autofluorescence,and higher signalto-background ratios.However,more challenges are expected before the successful translation of NIR-II probes from bench to bedside.This review provides a brief overview of targeted fluorescent probes under clinical evaluation and recent achievements in the field of NIR-II fluorescence imaging.In addition,we outline key considerations concerning the design of fluorescent probes for clinical translation.

Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium:Integration of herbal medicine,enzyme engineering,and nanotechnology

Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium(EF)and possess excellent therapeutic effects on various diseases.Encouragingly,in 2022,icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma(HCC)by National Medical Products Administration(NMPA)of China.Moreover,recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects.Nonetheless,both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content,poor bioavailability,and unfavorable in vivo delivery efficiency.Recently,various strategies,including enzyme engineering and nanotechnology,have been developed to increase productivity and activity,improve delivery efficiency,and enhance therapeutic effects of epimedium flavonoids.In this review,the structure-activity relationship of epimedium flavonoids is described.Then,enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed.The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized.Finally,the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.

Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma(HCC),such as surgical resection,transplantation,radiofrequency ablation,and chemotherapy are unsatisfactory,and therefore the exploration of powerful therapeutic strategies is urgently needed.Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects.Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC.Encouragingly,in 2022,icaritin soft capsules were approved by the National Medical Products Administration(NMPA)of China for the immunotherapy of advanced HCC.However,the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency.Recently,functionalized drug delivery systems including stimuli-responsive nanocarriers,cell membrane-coated nanocarriers,and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs,including the low bioavailability and limited delivery efficiency as well as side effects.Taken together,the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC.Herein,we compared the different preparation methods for icaritin,interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC,and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritinbased nanomedicines for advanced HCC immunotherapy.Finally,the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

Large animal ischemic stroke models: replicating human stroke pathophysiology

The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.

Precision medicine: In need of guidance and surveillance

Precision medicine,currently a hotspot in mainstream medicine,has been strongly promoted in recent years. With rapid technological development,such as next-generation sequencing,and fierce competition in molecular targeted drug exploitation,precision medicine represents an advance in science and technology; it also fulfills needs in public health care. The clinical translation and application of precision medicine-especially in the prevention and treatment of tumors-is far from satisfactory; however,the aims of precision medicine deserve approval. Thus,this medical approach is currently in its infancy; it has promising prospects,but it needs to overcome numbers of problems and deficiencies. It is expected that in addition to conventional symptoms and signs,precision medicine will define disease in terms of the underlying molecular characteristics and other environmental susceptibility factors. Those expectations should be realized by constructing a novel data network,integrating clinical data from individual patients and personal genomic background with existing research on the molecular makeup of diseases. In addition,multi-omics analysis and multi-discipline collaboration will become crucial elements in precision medicine. Precision medicine deserves strong support,and its development demands directed momentum. We propose three kinds of impetus(research,application and collaboration impetus) for such directed momentum toward promoting precision medicine and accelerating its clinical translation and application.

Functionalized Hydrogels for Articular Cartilage Tissue Engineering

Articular cartilage(AC)is an avascular and flexible connective tissue located on the bone surface in the diarthrodial joints.AC defects are common in the knees of young and physically active individuals.Because of the lack of suitable tissue-engineered artificial matrices,current therapies for AC defects,espe-cially full-thickness AC defects and osteochondral interfaces,fail to replace or regenerate damaged carti-lage adequately.With rapid research and development advancements in AC tissue engineering(ACTE),functionalized hydrogels have emerged as promising cartilage matrix substitutes because of their favor-able biomechanical properties,water content,swelling ability,cytocompatibility,biodegradability,and lubricating behaviors.They can be rationally designed and conveniently tuned to simulate the extracel-lular matrix of cartilage.This article briefly introduces the composition,structure,and function of AC and its defects,followed by a comprehensive review of the exquisite(bio)design and(bio)fabrication of func-tionalized hydrogels for AC repair.Finally,we summarize the challenges encountered in functionalized hydrogel-based strategies for ACTE both in vivo and in vitro and the future directions for clinical translation.

Modulating microRNAs in cancer: next-generation therapies

MicroRNAs(miRNAs)are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate a variety of biological and pathological processes.There is growing evidence demonstrating frequent dysregulation of microRNAs in cancer cells,which is associated with tumor initiation,development,migration,invasion,resisting cell death,and drug resistance.Studies have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment of a variety of diseases,especially cancer,due to their broad influence on multiple cellular processes.However,suboptimal delivery of the appropriate miRNA to the cancer sites,quick degradation by nucleases in the blood circulation,and off target effects have limited their research and clinical applications.Therefore,there is a pressing need to improve the therapeutic efficacy of miRNA modulators,while at the same time reducing their toxicities.Several delivery vehicles for miRNA modulators have been shown to be effective in vitro and in vivo.In this review,we will discuss the role and importance of miRNAs in cancer and provide perspectives on currently available carriers for miRNA modulation.We will also summarize the challenges and prospects for the clinical translation of miRNAbased therapeutic strategies.

The clinical prospect of FLASH radiotherapy

FLASH radiotherapy(FLASH-RT)is a new strategy for tumor treatment with an ultra-high dose rate of more than 40 Gy/s.Compared with conventional radiotherapy(CONV-RT),FLASH-RT has no different inhibitory effects on tumors but less damage to normal tissues,which is called the“spare”effect.The“spare”effect triggers our exploration of the great prospect of subverting conventional radiotherapy and its intricate mechanisms.Mitochondrial homeostasis,the immune microenvironment,or DNA integrity may potentially represent the primary breakthrough direction in understanding the mechanisms.Concurrently,it is imperative to advance timely clinical translation efforts.Clinical trials of FLASH-RT have progressed to Phase II in both the United States and Switzerland,with current findings suggesting that FLASH-RT achieves comparable efficacy to CONV-RT while mitigating side effects in select cancer cell types.While summarizing the existing FLASH experiments,this paper emphasizes the significance of clinical transformation and the challenges that will be faced and proposes possible solutions.

Pseudotyped lentiviral vectors:Ready for translation into targeted cancer gene therapy?

Gene therapy holds great promise for curing cancer by editing the deleterious genes of tumor cells,but the lack of vector systems for efficient delivery of genetic material into specific tumor sites in vivo has limited its full therapeutic potential in cancer gene therapy.Over the past two decades,increasing studies have shown that lentiviral vectors(LVs)modified with different glycoproteins from a donating virus,a process referred to as pseudotyping,have altered tropism and display cell-type specificity in transduction,leading to selective tumor cell killing.This feature of LVs together with their ability to enable high efficient gene delivery in dividing and non-dividing mammalian cells in vivo make them to be attractive tools in future cancer gene therapy.This review is intended to summarize the status quo of some typical pseudotypings of LVs and their applications in basic anti-cancer studies across many malignancies.The opportunities of translating pseudotyped LVs into clinic use in cancer therapy have also been discussed.

New idea to promote the clinical applications of stem cells or their extracellular vesicles in central nervous system disorders:Combining with intranasal delivery

The clinical translation of stem cells and their extracellular vesicles(EVs)-based therapy for central nervous system(CNS) diseases is booming. Nevertheless, the insufficient CNS delivery and retention together with the invasiveness of current administration routes prevent stem cells or EVs from fully exerting their clinical therapeutic potential. Intranasal(IN) delivery is a possible strategy to solve problems as IN route could circumvent the brain-blood barrier non-invasively and fit repeated dosage regimens. Herein, we gave an overview of studies and clinical trials involved with IN route and discussed the possibility of employing IN delivery to solve problems in stem cells or EVs-based therapy. We reviewed relevant researches that combining stem cells or EVs-based therapy with IN administration and analyzed benefits brought by IN route. Finally, we proposed possible suggestions to facilitate the development of IN delivery of stem cells or EVs.

Advances and perspective on the translational medicine of biodegradable metals

Biodegradable metals,designed to be safely degraded and absorbed by the body after fulfil the intended functions,are of particular interest in the 21st century.The marriage of advanced biodegradable metals with clinical needs have yield unprecedented possibility.Magnesium,iron,and zinc-based materials constitute the main components of temporary,implantable metallic medical devices.A burgeoning number of studies on biodegradable metals have driven the clinical translation of biodegradable metallic devices in the fields of cardiology and orthopaedics over the last decade.Their ability to degrade as well as their beneficial biological functions elicited during degradation endow this type of material with the potential to shift the paradigm in the treatment of musculoskeletal and cardiovascular diseases.This review provides an insight into the degradation mechanism of these metallic devices in specific application sites and introduces state-of-the-art translational research in the field of biodegradable metals,as well as highlighting some challenges for materials design strategies in the context of mechanical and biological compatibility.

Article Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid)porous scaffolds by three-dimensional printing Jing

Biodegradable polymer scaffolds combined with bioactive components which accelerate osteogenesis and angiogenesis have promise for use in clinical bone defect repair.The preclinical acute toxicity evaluation is an essential assay of implantable biomaterials to assess the biosafety for accelerating clinical translation.We have successfully developed magnesium(Mg)particles and beta-tricalcium phosphate(β-TCP)for incorporation into poly(lactic-co-glycolic acid)(PLGA)porous composite scaffolds(PTM)using low-temperature rapid prototyping three-dimensional-printing technology.The PTM scaffolds have been fully evaluated and found to exhibit excellent osteogenic capacity for bone defect repair.The preclinical evaluation of acute systemic toxicities is essential and important for development of porous scaffolds to facilitate their clinical translation.In this study,acute systemic toxicity of the PTM scaffolds was evaluated in mice by intraperitoneal injection of the extract solutions of the scaffolds.PTM composite scaffolds with different Mg andβ-TCP content(denoted as PT5M,PT10M,and PT15M)were extracted with different tissue culture media,including normal saline,phosphate-buffered saline,and serum-free minimum essential medium,to create the extract solutions.The evaluation was carried out following the National Standard.The acute toxicity was fully evaluated through the collection of extensive data,including serum/organs ion concentration,fluorescence staining,and in vivo median lethal dose measurement.Mg in major organs(heart,liver,and lung),and Mg ion concentrations in serum of mice,after intraperitoneal injection of the extract solutions,were measured and showed that the extract solutions of PT15M caused significant elevation of serum Mg ion concentrations,which exceeded the safety threshold and led to the death of the mice.In contrast,the extract solutions of PT5M and PT10M scaffolds did not cause the death of the injected mice.The median lethal dose of Mg ions in vivo for mice was determined for the first time in this study to be 110.66 mg/kg,and the safety level of serum magnesium toxicity in mice is 5.4 mM,while the calcium serum safety level is determined as 3.4 mM.The study was approved by the Animal Care and Use Committee of Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences(approval No.SIAT-IRB-170401-YGS-LYX-A0346)on April 5,2017.All these results showed that the Mg ion concentration of intraperitoneally-injected extract solutions was a determinant of mouse survival,and a high Mg ion concentration(more than 240 mM)was the pivotal factor contributing to the death of the mice,while changes in pH value showed a negligible effect.The comprehensive acute systemic toxicity evaluation for PTM porous composite scaffolds in this study provided a reference to guide the design and optimization of this composite scaffold and the results demonstrated the preclinical safety of the as-fabricated PTM scaffold with appropriate Mg content,strongly supporting the official registration process of the PTM scaffold as a medical device for clinical translation.

Translational Neuroscience and Clinics

Aims and Scope Translational Neuroscience and Clinics is an open access journal publishing articles focusing on information derived from human experimentation so as to optimise the communication between basic and clinical neuroscience.Articles deal with a wide range of topics including physiological,medical。

Current research trends of nanomedicines

Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment,nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects.Nanomedicines hold tremendous theranostic potential for treating,monitoring,diagnosing,and controlling various diseases and are attracting an unfathomable amount of input of research resources.Against the backdrop of an exponentially growing number of publications,it is imperative to help the audience get a panorama image of the research activities in the field of nanomedicines.Herein,this review elaborates on the development trends of nanomedicines,emerging nanocarriers,in vivo fate and safety of nanomedicines,and their extensive applications.Moreover,the potential challenges and the obstacles hindering the clinical translation of nanomedicines are also discussed.The elaboration on various aspects of the research trends of nanomedicines may help enlighten the readers and set the route for future endeavors.

Self-therapeutic metal-based nanoparticles for treating inflammatory diseases

Inflammatory diseases are key contributors to high mortality globally and adversely affect the quality of life.Current treatments include corticosteroids or nonsteroidal anti-inflammatories that may cause systemic toxicity and biologics that may increase the risk of infection.Composite nanoparticles that bear not only the drug payload but also targeting ligands for delivery to inflammation sites at lowered systemic toxicity are established in the nanomedicine field,but their relatively large size often leads to systemic clearance.Metal-based nanoparticles with intrinsic anti-inflammatory properties represent attractive alternatives.They are not only designed to be compact for crossing biological barriers(with the nanoparticle serving as a dual carrier and drug),but also support label-free tracking of their interactions with cells.The review commences with an outline of the common inflammatory diseases,inflammatory pathways involved,and conventional drug-loaded nanoparticles for anti-inflammation.Next,the review features the emerging applications of self-therapeutic metal-based nanoparticles(e.g.,gold,coper oxide,platinum,ceria,and zinc oxide)for managing inflammatory diseases in animals over the past three years,focusing on therapeutic outcomes and anti-inflammatory mechanisms.The review concludes with an outlook on the biodistribution,long-term toxicity,and clinical translation of self-therapeutic metalbased nanoparticles.

Scalable fabrication,compartmentalization and applications of living microtissues

Living microtissues are used in a multitude of applications as they more closely resemble native tissue physiology,as compared to 2D cultures.Microtissues are typically composed of a combination of cells and materials in varying combinations,which are dictated by the applications’design requirements.Their applications range wide,from fundamental biological research such as differentiation studies to industrial applications such as cruelty-free meat production.However,their translation to industrial and clinical settings has been hindered due to the lack of scalability of microtissue production techniques.Continuous microfluidic processes provide an opportunity to overcome this limitation as they offer higher throughput production rates as compared to traditional batch techniques,while maintaining reproducible control over microtissue composition and size.In this review,we provide a comprehensive overview of the current approaches to engineer microtissues with a focus on the advantages of,and need for,the use of continuous processes to produce microtissues in large quantities.Finally,an outlook is provided that outlines the required developments to enable large-scale microtissue fabrication using continuous processes.

Recent progress and challenges in the treatment of spinal cord injury

Spinal cord injury(SCI)disrupts the structural and functional connectivity between the higher center and the spinal cord,resulting in severe motor,sensory,and autonomic dysfunction with a variety of complications.The pathophysiology of sci is complicated and multifaceted,and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after ScI.Combinatory strategies targeting multiple aspects of scI pathology have achieved greater beneficial effects than individuai therapy alone.Although many problems and challenges remain,the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat scl.In this review,we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following scI at both the acute and chronic stages.In addition,we analyze the current status,remaining problems,and realistic challenges towards clinical translation.Finally,we consider the future of scI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice.Going forward,clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeuticbenefitinhumanswithscl.