Stimuli-Responsive Gene Delivery Nanocarriers for Cancer Therapy

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.

Engineered stem cells by emerging biomedical stratagems

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders.As the safety of stem cell transplantation having been demonstrated in numerous clinical trials,various kinds of stem cells are currently utilized in medical applications.Despite the achievements,the therapeutic benefits of stem cells for diseases are limited,and the data of clinical researches are unstable.To optimize tthe effectiveness of stem cells,engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities,paving the way for the next generation of stem cell therapies.This review offers a detailed analysis of engineered stem cells,including their clinical applications and potential for future development.We begin by briefly introducing the recent advances in the production of stem cells(induced pluripotent stem cells(ipsCs),embryonic stem cells(ESCs),mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs).Furthermore,we present the latest developments of engineered strategies in stem cells,including engineered methods in molecular biology and biomaterial fields,and their application in biomedical research.Finally,we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.

基于微流控的仿生细胞封装

将细胞封装在生物材料中用于器官修复或疾病治疗是一个新兴领域.目前,微流控技术被用于精确控制封装细胞的数量、大小和支架结构.微流控技术提供了设计生物仿生形态的能力,增强封装细胞的活性和功能,从而提高疾病治疗的效果.本文报道了微流控技术在仿生细胞封装方面的最新进展.我们首先简要概述了各种天然衍生的促进细胞功能的仿生结构,如受到细胞、植物、动物和自然反应启发的结构;之后讨论了基于微技术的最新细胞封装方法,并详细描述了相关过程;最后提出了仿生细胞封装在疾病治疗和临床应用中面临的挑战和未来方向.

Orthotopic implantable liver decellularized scaffold for acute liver failure

Decellularized scaffolds have an irreplaceable role in the development of tissue engineering.Challenges in this field are concentrated on shaping macro-scale constructs and maintaining blood flow.Here,we establish a whole liver perfused decellularized scaffold cultured with hepatocytes for transplantable bioengineered liver construction.Owing to retained intact gross morphology of liver,geometric structure and biomechanical environment can support whole liver lobe transplantation.Besides,unremoved extracellular matrix(ECM)and vascular net-works can delivery continuous nutrient for cell adhesion.Based on recellularized bioengineering liver scaffold,we have demonstrated its excellent hepatic functions when it orthotopic implanted in acute liver failure(ALF)rats,along with the prolonged survival rate and improved biochemical indicators.These outstanding properties indicate that the orthotopic implantable liver scaffold has broad clinical application prospects in the treatment of ALF and other regeneration diseases.

Transplantation of Mesenchymal Stem Cells Attenuates Acute Liver Failure in Mice via an Interleukin-4-dependent Switch to the M2 Macrophage Anti-inflammatory Phenotype

Background and Aims:Transplantation of mesenchymal stem cells(MSCs)derived from bone marrow(BM)is an alternative treatment of acute liver failure(ALF)mainly be-cause of the resulting anti-inflammatory activity.It is not known how MSCs regulate local immune responses and liver regeneration.This study explored the effects of MSCs on hepatic macrophages and the Wnt signaling pathway in ALF.Methods:MSCs were isolated from BM aspirates of C57BL/6J mice,and transplanted in mice with ALF induced by D-galactosamine(D-Gal).The proliferation of hepato-cytes was assayed by immunohistochemical(IHC)staining of Ki-67 and proliferating cell nuclear antigen(PCNA).The levels of key proteins in the Wnt signaling pathway were assayed by western blotting and cytokines were determined enzyme-linked immunosorbent assays(ELISAs).A mac-rophage polarization assay characterized the M1/M2 ratio.The potential role of interleukin-4(IL-4)in the biological ac-tivity of MSCs was determined by silencing of IL-4.Results:Transplantation of allogeneic MSCs significantly attenuated D-Gal-induced hepatic inflammation and promoted liver re-generation.MSC transplantation significantly promoted a phenotypic switch from proinflamatory M1 macrophages to anti-inflammatory M2 macrophages,leading to significant Wnt-3a induction and activation of the Wnt signaling path-way in mice with D-Gal-induced ALF.Of the paracrine fac-tors secreted by MSCs(G-CSF,IL-6,IL-1 beta,IL-4,and IL-17A),IL-4 was specifically induced following transplantation in the ALF model mice.The silencing of IL-4 significantly ab-rogated the phenotypic switch to M2 macrophages and the protective effects of MSCs in both the ALF model mice and a co-culture model in an IL-4 dependent manner.Conclu-sions:In vivo and in vitro studies showed that MSCs ame-liorated ALF through an IL-4-dependent macrophage switch toward the M2 anti-inflammatory phenotype.The findings may have clinical implications in that overexpression of IL-4 may enhance the therapeutic effects of allogeneic MSC transplantation in the treatment of ALF.

Developing tissue engineering strategies for liver regeneration

The regenerative function of liver can be destroyed by viral infection,drug poisoning and tumorigenesis,resulting in irreversible damage.Numerous approaches in promoting liver repair intend to replace liver transplantation,which is faced with a shortage of donors.Owing to the significant advantages in cell programming and bioscaf-fold engineering,liver tissue engineering is considered to be the most promising alternative for mimicking liver microstructure,maintaining hepatic function or implanting whole liver.Cell sources gradually develop from pri-mary hepatocytes,tumor cells,stem cell-induced cells to multiple cell coculture formats,spheroids and organoids,which have realized the improvement of cell function,overcome the problem of large-scale cell expansion and avoid the risk of immune rejection.Scaffolds,biocompatible materials are applied as cell carriers,and decel-lularized scaffolds and three-dimensional bioprinting liver pipeline structures are also used to accelerate cell colonization and proliferation.We enumerate sufficient research concerning liver tissue engineering in this re-view,including single and multiple cell sources,implantable and extracorporeal scaffold materials,and so on,providing critical conclusions and future implications of tissue engineering in liver regenerative applications.

Acoustofluidics for cell patterning and tissue engineering

Acoustofluidics has been a promising approach using sound waves to manipulate particles and actuate fluids in biomedical applications.It usually generates acoustic radiation force and acoustic streaming to initiate diffraction,reflection and interference,building up a pressure distribution to facilitate accurate manipulation of micro-or nano-scale particles and fluids.Owing to its remarkable contact-free and biocompatible advantages,acoustoflu-idics has been used in high-throughput cell analysis,size-controllable organoid structures,and functional tissue mimics.We enumerate the basic concepts and the sufficient research of acoustofluidics in precise patterning and tissue engineering in this review,including the design and function of four typical acoustofluidic devices,var-ious forms of cell patterning and 3D tissue engineering.Meanwhile,we outlined current challenges and future directions of acoustofluidics in biomedicine and tissue engineering.