Hydrogen sulfide responsive nanoplatforms: Novel gas responsive drug delivery carriers for biomedical applications

Hydrogen sulfide(H_(2)S)is a toxic,essential gas used in various biological and physical processes and has been the subject of many targeted studies on its role as a new gas transmitter.These studies have mainly focused on the production and pharmacological side effects caused by H_(2)S.Therefore,effective strategies to remove H_(2)S has become a key research topic.Furthermore,the development of novel nanoplatforms has provided new tools for the targeted removal of H_(2)S.This paper was performed to review the association between H_(2)S anddisease,relatedH_(2)S inhibitory drugs,aswell as H_(2)S responsive nanoplatforms(HRNs).This review first analyzed the role of H_(2)S in multiple tissues and conditions.Second,common drugs used to eliminate H_(2)S,as well as their potential for combination with anticancer agents,were summarized.Not only the existing studies on HRNs,but also the inhibition H_(2)S combined with different therapeutic methods were both sorted out in this review.Furthermore,this review provided in-depth analysis of the potential of HRNs about treatment or detection in detail.Finally,potential challenges of HRNs were proposed.This study demonstrates the excellent potential of HRNs for biomedical applications.

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.

Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors.Tumor cells generally display the higher oxidative level than normal cells,and also displayed the heterogeneity in terms of redox homeostasis level.We previously found that the disulfide bond-linkage demonstrates surprising oxidationsensitivity to form the hydrophilic sulfoxide and sulphone groups.Herein,we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a(PPa)to achieve light-activatable cascade drug release and enhance therapeutic efficacy.The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor,but also respond to the exogenous oxidant(singlet oxygen)elicited by photosensitizers.Once the prodrug nanoparticles(NPs)are activated under irradiation,they would undergo an oxidative self-strengthened process,resulting in a facilitated drug cascade release.The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation.In vivo,the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site.The PPa@PTXS-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4 T1 tumors.Therefore,this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.

Nanoplatforms for Sepsis Management: Rapid Detection/Warning, Pathogen Elimination and Restoring Immune Homeostasis

Sepsis,a highly life-threatening organ dysfunction caused by uncontrollable immune responses to infection,is a leading contributor to mortality in intensive care units.Sepsis-related deaths have been reported to account for 19.7%of all global deaths.However,no effective and specific therapeutic for clinical sepsis management is available due to the complex pathogenesis.Concurrently eliminating infections and restoring immune homeostasis are regarded as the core strategies to manage sepsis.Sophisticated nanoplatforms guided by supramolecular and medicinal chemistry,targeting infection and/or imbalanced immune responses,have emerged as potent tools to combat sepsis by supporting more accurate diagnosis and precision treatment.Nanoplatforms can overcome the barriers faced by clinical strategies,including delayed diagnosis,drug resistance and incapacity to manage immune disorders.Here,we present a comprehensive review highlighting the pathogenetic characteristics of sepsis and future therapeutic concepts,summarizing the progress of these well-designed nanoplatforms in sepsis management and discussing the ongoing challenges and perspectives regarding future potential therapies.Based on these state-of-the-art studies,this review will advance multidisciplinary collaboration and drive clinical translation to remedy sepsis.

Soft Mesoporous Organosilica Nanoplatforms Improve Blood Circulation,Tumor Accumulation/Penetration,and Photodynamic Efficacy

To date,the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration.Herein,a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared,denoted SMONs-HA-Cy5.5,and comparative studies between SMONs-HA-Cy5.5(24.2 MPa)and stiff counterparts(79.2 MPa)are conducted.Results indicate that,apart from exhibiting a twofold increase in tumor cellular uptake,the soft nanoplatforms also display a remarkable pharmacokinetic advantage,resulting in considerably improved tumor accumulation.Moreover,SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration,achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts.Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels,diffuse farther in the dense extracellular matrix,and reach deeper tumor tissues compared to the stiff ones.Specifically,the soft nanoplatforms generate a 16-fold improvement(43 vs.2.72μm)in diffusion distance in tumor parenchyma.Based on the significantly improved blood circulation and tumor accumulation/penetration,a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5.The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones.

Recent deveolpment of multifunctional responsive gas-releasing nanoplatforms for tumor therapeutic application

Gas therapy(GT)exhibits great potential for clinical application due to its high therapeutic efficiency,low systemic side effects,and biosafety,thereinto,a multifunctional nanoplatform is generally needed for controllable gas release and precise delivery to tumor tissue.In this review,the recent development of multifunctional nanoplatforms for efficient tumor delivery of stimuliresponsive gas-releasing molecules(GRMs),which could be triggered by either exogenous physical or endogenous tumor microenvironment(TME)is summarized.The reported therapeutic gas molecules,including oxygen(O_(2)),hydrogen sulfide(H_(2)S),nitric oxide(NO),hydrogen(H_(2)),and carbon monoxide(CO),etc.,could directly influence or change the pathological status.Additionally,abundant nanocarriers have been employed for gas delivery into cancer region,such as mesoporous silica nanoparticles(MSNs),metal-organic frameworks(MOFs),two-dimensional(2D)nanomaterials,and liposomes,as well as nonnanocarriers including inorganic and organic nanoparticles.In the end,the outlooks of current challenges of GT and GRMs delivery nanoplatforms as well as the prospects of future clinical applications are proposed.

Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor

Photodynamic therapy(PDT)has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death(ICD)effects.However,the strategy is limited in the innate hypoxic tumor microenvironment.There are two key elements for the realization of enhanced PDT:specific cellular uptake and release of the photosensitizer in the tumor,and a sufficient amount of oxygen to ensure photodynamic efficiency.Herein,self-oxygenated biomimetic nanoparticles(CS@M NPs)co-assembled by photosensitizer prodrug(Ce6-S-S-LA)and squalene(SQ)were engineered.In the treatment of triple negative breast cancer(TNBC),the oxygen carried by SQ can be converted to reactive oxygen species(ROS).Meanwhile,glutathione(GSH)consumption during transformation from Ce6-S-S-LA to chlorin e6(Ce6)avoided the depletion of ROS.The co-assembled(CS NPs)were encapsulated by homologous tumor cell membrane to improve the tumor targeting.The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin(CRT)and high mobility group protein B1(HMGB1),and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha(HIF-1α)-CD39-CD73-adenosine a2a receptor(A2AR)pathway,which not only promoted the maturation of dendritic cells(DC)and the presentation of tumor specific antigens,but also induced effective immune infiltration of tumors.Overall,the integrated nanoplatform implements the concept of multiple advantages of tumor targeting,reactive drug release,and synergistic photodynamic therapy-immunotherapy,which can achieve nearly 90%tumor suppression rate in orthotopic TNBC models.

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy

Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES capture.Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage.The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.

稀土纳米材料在脑肿瘤成像和治疗中的研究进展

脑肿瘤是最致命的疾病之一,由于缺乏有效的诊断和治疗手段导致其预后差、复发率高,患者5年生存率低。因此,许多研究人员致力于开发非侵入性高分辨率成像技术以获得脑肿瘤的解剖结构和信息,实现精准的早期诊断,并开发新型高效的治疗方式,以及诊断、治疗一体化的新范式。稀土纳米材料(Rare earth-based nanoparticles,RENPs)因其独有的优势被广泛应用于疾病诊断、药物输送、肿瘤治疗和生物成像等领域。RENPs具有独特的光学、磁学特性和高X射线吸收能力,可通过荧光成像、磁共振成像和计算机断层扫描成像对脑肿瘤进行高分辨率成像。RENPs的发射光可调谐,特别是其近红外第二生物学窗口(Second near-infrared,NIR-Ⅱ,1000~1700 nm)的发射具有较强的组织穿透性,低的背景荧光干扰,适合用于荧光成像探针及光响应性治疗的光刺激。重要的是,RENPs还具有优异的生物相容性以及表面易功能化等特点,可与抗体、肽和药物等生物大分子结合,以增强穿越血脑屏障(Blood-brain barrier,BBB)的能力,有利于靶向治疗和高对比度成像。因此,本综述重点介绍了RENPs在脑肿瘤成像和治疗领域的设计策略和应用,最后探讨了RENPs在肿瘤诊疗领域现有的挑战并对其未来的发展进行了展望。

ICG@ZIF-8:One-step encapsulation of indocyanine green in ZIF-8 and use as a therapeutic nanoplatform

How to fabricate zeolitic imidazole framework-8 （ZIF-8） based therapeutic nanoplatform will be of significance in biomedicine considering its good biocompatibility. Herein, we report a one-step encapsulation of indocyanine green （ICG） in ZlF-8 nanoparticles （NPs）. The as-prepared ICG@ZIF-8 NPs possess an absorption band in the near infrared region and have the good photothermal conversion efficiency. The in vivo and in vitro studies show that, after loading chemotherapy agent hydrophobic doxorubicin （DOX）, ICG@ZIF-8-DOX NPs exhibit the chem-and photothermal synergistic therapy for tumor. In addition, it is found that the embedded ICG molecules in ICG@ZlF-8 NPs can be disassociated and released into the solution upon the 808 nm laser irradiation, demonstrating that as-prepared ICG@ZIF-8 NPs can also be used as the optical imaging probe to trace the degradability behavior of resulting NPs in future

A novel clustered SPIO nanoplatform with enhanced magnetic resonance T2 relaxation rate for micro-tumor detection and photothermal synergistic therapy

Construction of micro tumor sensitive theranostic nanoagents that can increase the accuracy of imaging diagnosis and boost the therapeutic efficacy has been demonstrated for a promising approach for diagnosis and treatment of cancer.Herein,we reported a novel super-paramagnetic iron oxide(SPIO)based nanoplatform that possess significantly enhanced magnetic resonance property and photothermal effect for tumor theranostic purpose.This polyethylene glycol with four phenylboronic acid(PEG-B4)/CNTs@porphyrin(ph)/SPIO(BCPS)nanoplatform was simply prepared via integrated SPIO,ph,and a novel dendrimer with PEG liner and four PBA groups(PEG-B4)on the surface of carbon nanotubes(CNTs).Subsequently,a significant T2 relaxation rate enhanced can be achieved by the reduced accessibility of water to SPIO clustering.Moreover,the synergetic enhanced photothermal from BCPS nanoplatform contributed to better photothermal effect for cancer therapy.Furthermore,the targeting ability to sialic acid overexpressed tumor was further introduced from phenylboronic acid from PEG-B4.We showed that BCPS nanoplatform could not only selectively identify solid tumors and detect micro-sized metastatic tumor(1 mm)in the liver,but also effectively ablate tumors in a xenograft model,thereby achieving a complete cure rate of 100%at low laser dose.Our results highlight the potential of BCPS nanoplatform for accurate micro-tumor diagnosis and effective tumor therapy.

Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy

CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment.However,development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges.Herein,a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system(NPCSPt/pEZH2)and synergistic treatment of prostate cancer.The pEZH2/Pt(II)could be effectively triggered to unpack/release from NPCSPt/pEZH2 in a chain-shattering manner in cancer cells.The EZH2 gene disruption efficiency could be achieved up to 32.2%of PC-3 cells in vitro and 21.3%of tumor tissues in vivo,leading to effective suppression of EZH2 protein expression.Moreover,significant H3K27me3 downregulation could occur after EZH2 suppression,resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II)to nuclear DNA for enhanced apoptosis.Taken together,substantial proliferation inhibition of prostate cancer cells and further 85.4%growth repression against subcutaneous xenograft tumor could be achieved.This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery,but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.

Fabrication of a Magnetite Nanoparticle-loaded Polymeric Nanoplatform for Magnetically Guided Drug Delivery

We developed a magnetite nanoparticle-loaded polymeric nanoplatform for magnetically guided 10- hydroxycamptothecin（HCPT） delivery. The nanoplatform was fabricated by simultaneously incorporating magnetite nanoparticles（NPs） and HCPT into the polymer micelle self-assembled from methoxy polyethylene glycolpoly（D,L-lactide-co-glycolide）（MPEG-PLGA） copolymer. Successful loading of HCPT into the nanoplatform was confirmed by Fourier transform infrared（FTIR） spectroscopy. Subsequently, we examined the in vitro antitumor efficacy of free HCPT and nanoplatform against three different cancer cell lines HeLa, A549 and HepG2. Flow cytometric analysis was condkt ,ucted to reveal the cell apoptosis caused by free HCPT and nanoplatform. Finally, the magnetic targeting property of the nanoplatform was evaluated by a self-designed in vitro experiment.

Liposome-based multifunctional nanoplatform as effective therapeutics for the treatment of retinoblastoma

Photothermal therapy has the characteristics of minimal invasiveness,controllability,high efficiency,and strong specificity,which can effectively make up for the toxic side effects and tumor resistance caused by traditional drug treatment.However,due to the limited tissue penetration of infrared light,it is difficult to promote and apply in clinical practice.The eye is the only transparent tissue in human,and infrared light can easily penetrate the eye tissue,so it is expected that photothermal therapy can be used to treat fundus diseases.Here in,a new nano-platform assembled by liposome and indocyanine green(ICG) was used to treat retinoblastoma.ICG was assembled in liposomes to overcome some problems of ICG itself.For example,ICG is easily quenched,self-aggregating and instability.Moreover,liposomes can prevent free ICG from being cleared through the systemic circulation.The construction of the nano-platform not only ensured the stability of ICG in vivo,but also realized imaging-guide photothermal therapy,which created a new strategy for the treatment of retinoblastoma.

Fe-Co/ZIF-8@SLC-0111-HA复合纳米平台加强肿瘤化学动力学的可行性

背景:常用金属离子的低催化活性与缺乏靶向性等问题严重限制了化学动力学疗法在肿瘤治疗中的应用。另外,虽然通过对复合纳米平台进行表面功能化来赋予其靶向肿瘤的功能,但是肿瘤细胞内酸性不足也严重削弱了化学动力学疗法的疗效。目的:制备新型复合纳米平台,评估其在细胞水平上增强化学动力学疗法的可行性。方法:通过离子交换反应和自组装作用合成了掺杂二价铁离子和二价钴离子的载SLC-0111(一种碳酸酐酶9抑制剂)沸石咪唑骨架-8(Fe-Co/ZIF-8@SLC-0111),并在表面加载透明质酸,得到目标纳米颗粒Fe-Co/ZIF-8@SLC-0111-HA(记为FC-S),同时合成不载SLC-0111的纳米颗粒Fe-Co/ZIF-8-HA(记为FC)。测试FC-S的粒径、Zeta电位、表面形貌、体外活性氧产生、消耗谷胱甘肽的能力。分别以人骨肉瘤细胞MG-63和小鼠成纤维细胞L929为实验对象,采用CCK-8法检测FC-S的细胞毒性。以人骨肉瘤细胞MG-63为实验对象,检测FC-S的细胞内化;在加入H_(2)O_(2)的情况下,FC-S、FC对细胞内pH值、碳酸酐酶9蛋白表达、细胞活性与凋亡、细胞内活性氧与谷胱甘肽含量、细胞线粒体膜电位的影响。结果与结论:①FC-S具有菱形十二面体结构,尺寸均匀,分散良好,平均粒径为323 nm,Zeta电位约为-11.1 mV,体外可产生活性氧并消耗谷胱甘肽。②FC-S以时间依赖的方式在MG-63细胞内累积,并且能成功从溶酶体中逃逸。当FC-S质量浓度≤20μg/mL时对MG-63细胞与L929细胞无明显的细胞毒性,后续实验选择20μg/mL FC-S作用于MG-63细胞。③与FC组比较,FC-S组MG-63细胞内碳酸酐酶9蛋白表达降低(P<0.01)、细胞内酸性环境增强、细胞内活性氧含量增加(P<0.001)、细胞线粒体损伤加重、死细胞数量增加、细胞凋亡率升高(P<0.001)。④结果表明,FC-S复合纳米平台能够有效改善肿瘤细胞内弱酸性微环境、提升胞内活性氧产生水平,增强化学动力学疗法的疗效。

Nanotheranostics:A powerful next-generation solution to tackle hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is an epidemic burden and remains highly prevalent worldwide.The significant mortality rates of HCC are largely due to the tendency of late diagnosis and the multifaceted,complex nature of treatment.Meanwhile,current therapeutic modalities such as liver resection and transplantation are only effective for resolving early-stage HCC.Hence,alt-ernative approaches are required to improve detection and enhance the efficacy of current treatment options.Nanotheranostic platforms,which utilize biocompatible nanoparticles to perform both diagnostics and targeted delivery,has been considered a potential approach for cancer management in the past few decades.Advancement of nanomaterials and biomedical engineering techniques has led to rapid expansion of the nanotheranostics field,allowing for more sensitive and specific diagnosis,real-time monitoring of drug delivery,and enhanced treatment efficacies across various malignancies.The focus of this review is on the applications of nanotheranostics for HCC.The review first explores the current epidemiology and the commonly encountered obstacles in HCC diagnosis and treatment.It then presents the current technological and functional advancements in nanotheranostic technology for cancer in general,and then specifically explores the use of nanotheranostic modalities as a promising option to address the key challenges present in HCC management.

可释放一氧化氮纳米材料的研究进展

一氧化氮(NO)是一种内源性双原子分子,在许多生理学和病理学过程中起了关键的调节作用,包括血管平滑肌松弛、免疫反应、神经传递、呼吸作用、细胞凋亡等。NO的生理调节作用在很大程度上依赖于NO释放的位置、时间以及剂量。开发出能够储存NO并且在指定的地点和时间释放需求量的NO的纳米运输平台是非常重要的研究课题。此篇综述,主要介绍近期我们课题组和其他研究人员在NO控制释放以及生物学应用的研究进展。本文首先概述了几类具有应用前景的外源性NO供体,如偶氮二醇烯、亚硝基硫醇、硝基苯和金属亚硝酰化合物。然后,重点讨论了结合NO供体和纳米平台在控制释放NO和生物医学的潜在应用。

基于超支化聚乙烯亚胺的双/多模态成像造影剂的研究进展

分子影像学技术作为癌症早期诊断的重要手段,其主要在组织、细胞和亚细胞水平上显示活体生理学变化,并进一步对其生物学行为进行定性和定量研究。目前,现代分子影像学技术包括X射线断层摄影术(CT)、光声成像(PA)、磁共振成像(MR)、荧光成像(FL)、单光子发射计算机断层显像(SPECT)和正电子发射型计算机断层显像(PET)等。各单一成像模式均存在优缺点,在空间分辨率、软组织分辨率、灵敏度及准确性等方面无法提供综合全面的信息以诊断及监测癌症。双/多模态成像模式的构建可极大地弥补以上缺陷,通过结合各单模态成像技术的优势来全面地反映癌症的发生、发展。因此,双/多模态造影剂成为研究热点。目前,在众多纳米造影剂中,超支化聚乙烯亚胺由于优良的结构及理化性质,外围基团可进行功能化修饰,内部空腔可负载多种有机/无机化合物,其作为纳米造影剂的优良平台被广泛使用。对超支化聚乙烯亚胺外围基团修饰聚乙二醇、叶酸、透明质酸可提高其在体内的生物相容性及组织特异性,进一步经螯合剂负载金属离子、包裹或稳定金属及金属氧化物纳米颗粒,可有效整合各种成像元素,以实现双/多模态成像。基于超支化聚乙烯亚胺的平台作用,可增强成像元素的生物相容性、组织特异性、肿瘤富集度,构建的基于超支化聚乙烯亚胺的双/多模态成像造影剂在生物医学成像领域具有广阔的应用前景。针对癌症的早期精确诊断,本文重点介绍了基于超支化聚乙烯亚胺的双/多模态成像造影剂的最新研究进展,对目前报道的基于超支化聚乙烯亚胺的双/多模态成像造影剂的构建及生物医学应用进行总结,涵盖CT/MR成像、CT/PA成像、SPECT/CT成像、PET/MR成像、FL/MR成像及三模态成像,为新型智能化纳米造影剂的构建提供参考。

A coating strategy on titanium implants with enhanced photodynamic therapy and CO-based gas therapy for bacterial killing and inflammation regulation

Antimicrobial photodynamic therapy(aPDT)has been considered a noninvasive and effective modality against the bacterial infection of peri‑implantitis,especially the aPDT triggered by near-infrared(NIR)light due to the large penetration depth in tissue.However,the complexity of hypoxia microenvironments and the distance of aPDT sterilization still pose challenges before realizing the aPDT clinical application.Due to the long lifespan and transmission distance of therapeutic gas molecules,we design a multi-functional gas generator that combines aPDT as well as O_(2) and CO gas release function,which can solve the problem of hypoxia(O_(2))in PDT and the problem of inflammation regulation(CO)in the distal part of peri‑implant inflammation under near-infrared(NIR)irradiation.In the composite nanoplatform that spin-coated on the surface of titanium implants,up-conversion nanoparticles(UCNPs)were involved in converting the NIR to visible,which further excites the partially oxidized stannic sulfide(SnS_(2)),realizing the therapeutic gas release.Indocyanine green(ICG)was further integrated to enhance the aPDT performance(Ti-U@SnS_(2)/I).Therefore,reactive oxygen species(ROS),CO,and O_(2) can be controllably administered via a composite nano-platform mediated by a single NIR light(808 nm).This implant surface modification strategy could achieve great self-enhancement antibacterial effectiveness and regulate the lingering questions,such as relieving the anoxic microenvironment and reaching deep infection sites,providing a viable antibiotic-free technique to combat peri‑implantitis.

Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade(ICB)monotherapy.However,combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery.Herein,based on a universal triterpene template and the anticancer active agent ursolic acid(UA),a cytomembrane-coated biomimetic delivery nanoplatform(UR@M)prepared by the selfassembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma(HCC)treatment.UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting,and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects.UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway,which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1.The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression.Overall,the UA-templated strategy“killed three birds with one stone”by establishing a self-assembly nanosystem,inducing tumor cell death,and promoting synergistic immunostimulation for HCC treatment.