A non-viral gene therapy for melanoma by staphylococcal enterotoxin A

Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to tumor site provides a promising option for reducing the systemic toxicity.Here,we constructed an iRGD peptide(H-[Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys]-NH_(2))modified nanoparticle(iDPP)to deliver plasmids encoding SEA for melanoma treatment.The iDPP/SEA nanocomplexes efficiently mediated SEA expression in B16-F10 cells in vivo and in vitro and induced the activation of lymphocytes and maturation of murine bone marrow-derived dendritic cells(BMDCs)in vitro.In the subcutaneous B16-F10 melanoma model,the iDPP/SEA nanocomplexes could effectively enhance immune response and T lymphocytes infiltration in tumor site after intravenous administration,thereby considerably decreased melanoma growth.Meanwhile,no obvious adverse effect was observed after intravenous administration of the iDPP/SEA nanocomplexes in vivo.Our findings demonstrated that gene therapy of SEA is a potential candidate for melanoma treatment.

Lidocaine hydrochloride loaded isomaltulose microneedles for efficient local anesthesia of the skin

Lidocaine hydrochloride(LIDH) as an anesthetic is widely used in local anesthesia. Dissolving microneedles(MNs) have great application value in the field of skin anesthesia. However, the limited drug-loading of dissolving MNs is an existing challenge that affects clinical use. In this study, we have screened isomaltulose(ISO) as the proper matrix material for the MNs by using molecular dynamics(MD) simulation. Our findings indicate that ISO has good compatibility with LIDH, and the LIDH-loaded ISO MNs(LI-MNs) have high drug-loading capacity. The drug-loading capacity of LI-MNs could reach 80%, and it could effectively puncture the skin. In addition, the preparation method of customized LI-MNs was established based on three-dimensional(3D) printing technology. It was shown that the administration time of LI-MNs could be controlled within 3 min. Also, the LI-MNs were able to provide the local anesthetic efficacy within2 min and sustained for more than 2 h. Significantly, LI-MNs had more efficient drug efficacy compared to the topical creams and the majority of existing LIDH-loaded dissolving MNs. They even provided a longer duration of action than the injections. Overall, the LI-MNs with high drug-loading have a promising application prospect.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Strategies for improving adipose-derived stem cells for tissue regeneration

Adipose-derived stem cells(ADSCs)have promising applications in tissue regeneration.Currently,there are only a few ADSC products that have been approved for clinical use.The clinical application of ADSCs still faces many challenges.Here,we review emerging strategies to improve the therapeutic efficacy of ADSCs in tissue regeneration.First,a great quantity of cells is often needed for the stem cell therapies,which requires the advanced cell expansion technologies.In addition cell-derived products are also required for the development of‘cell-free’therapies to overcome the drawbacks of cell-based therapies.Second,it is necessary to strengthen the regenerative functions of ADSCs,including viability,differentiation and paracrine ability,for the tissue repair and regeneration required for different physiological and pathophysiological conditions.Third,poor delivery efficiency also restricts the therapeutic effect of ADSCs.Effective methods to improve cell delivery include alleviating harsh microenvironments,enhancing targeting ability and prolonging cell retention.Moreover,we also point out some critical issues about the sources,effectiveness and safety of ADSCs.With these advanced strategies to improve the therapeutic efficacy of ADSCs,ADSC-based treatment holds great promise for clinical applications in tissue regeneration.

Bioprinting of skin constructs for wound healing

Extensive burns and full-thickness skin wounds are difficult to repair. Autologous split-thickness skin graft (ASSG) is still used as the gold standard in the clinic. However, the shortage of donor skin tissues is a serious problem. A potential solution to this problem is to fabricate skin constructs using biomaterial scaffolds with or without cells. Bioprinting is being applied to address the need for skin tissues suitable for transplantation, and can lead to the development of skin equivalents for wound healing therapy. Here, we summarize strategies of bioprinting and review current advances of bioprinting of skin constructs. There will be challenges on the way of 3D bioprinting for skin regeneration, but we still believe bioprinting will be potential skills for wounds healing in the foreseeable future.

Nerve transfer with 3D-printed branch nerve conduits

Background:Nerve transfer is an important clinical surgical procedure for nerve repair by the coaptation of a healthy donor nerve to an injured nerve.Usually,nerve transfer is performed in an end-to-end manner,which will lead to functional loss of the donor nerve.In this study,we aimed to evaluate the efficacy of 3D-printed branch nerve conduits in nerve transfer.Methods:Customized branch conduits were constructed using gelatine-methacryloyl by 3D print-ing.The nerve conduits were characterized both in vitro and in vivo.The efficacy of 3D-printed branch nerve conduits in nerve transfer was evaluated in rats through electrophysiology testing and histological evaluation.Results:The results obtained showed that a single nerve stump could form a complex nerve network in the 3D-printed multibranch conduit.A two-branch conduit was 3D printed for transferring the tibial nerve to the peroneal nerve in rats.In this process,the two branches were connected to the distal tibial nerve and peroneal nerve.It was found that the two nerves were successfully repaired with functional recovery.Conclusions:It is implied that the two-branch conduit could not only repair the peroneal nerve but also preserve partial function of the donor tibial nerve.This work demonstrated that 3D-printed branch nerve conduits provide a potential method for nerve transfer.

3D printing of functional nerve guide conduits

Nerve guide conduits(NGCs),as alternatives to nerve autografts and allografts,have been widely explored as an advanced tool for the treatment of peripheral nerve injury.However,the repairing efficiency of NGCs still needs significant improvements.Functional NGCs that provide a more favorable microenvironment for promoting axonal elongation and myelination are of great importance.In recent years,3D printing technologies have been widely applied in the fabrication of customized and complex constructs,exhibiting great potential for tissue engineering applications,especially for the construction of functional NGCs.In this review,we introduce the 3D printing technologies for manufacturing functional NGCs,including inkjet printing,extrusion printing,stereolithographybased printing and indirect printing.Further,we summarize the current methods and strategies for constructing functional NGCs,such as designing special conduit architectures,using appropriate materials and co-printing with different biological cues.Finally,the challenges and prospects for construction of functional NGCs are also presented.