The accurate localization of fluorescent nanoparticle Au-Ft in nu/nu mice kidney

Au-Ft,as a green synthesized nanoparticle,is composed of a ferritin nanocage enclosing a pair of Au nanoclusters inside.Our previous study has demonstrated that Au-Ft can be an excellentfluorescent probe for whole body imaging of mice with kidney specific targeting.But,the accuratelocalization of Au-Ft in kidney is still absent.In the current study,we detected and assessed the cellular and subcellular localization of Au-Ft in renal cortex and medulla of nu/nu mice after tailvein injection by using Nuance optical system(CRi,Woburn,USA)and inForm intelligent image analysis soft ware based on single cell segmentation.We obtained the fluorescence intensity and cellular location of kidney-targeting Au-Ft probe in particular cell of renal glomerulus or renaltubules,which provided valuable proofs to clarify the mechanism of Au-Ft selective enrichment in kidney and the associated metabolic processes.

精准设计的纳米机器药物及其抗肿瘤应用

纳米医药是当今生物和医学研究最具创新活力的领域之一,尤其是在恶性肿瘤等复杂难治疾病的治疗中展现出广阔的应用前景.随着纳米生物技术近年来的快速发展,能够在活体环境执行精密、复杂操作的纳米生物机器受到高度关注.本文总结了我们团队在抗肿瘤纳米机器药物方面的科研工作,从精准设计、体内操控和创新性治疗等方面,系统性介绍了基于核酸、多肽、膜结构等生物模块的纳米机器药物设计策略,讨论了不同类型纳米机器药物在肿瘤治疗中的优势,并结合当前肿瘤临床治疗的重点发展方向,讨论了纳米机器药物对治疗范式创新的潜在推动作用.

Self-assembly of CXCR4 antagonist peptide-docetaxel conjugates for breast tumor multi-organ metastasis inhibition

As a representative chemotherapeutic drug,docetaxel(DTX)has been used for breast cancer treatment for decades.However,the poor solubility of DTX limits its efficacy,and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4(CXCR4)expression during the treatment.Herein,we conjugated CXCR4 antagonist peptide(CTCE)with DTX(termed CTCE-DTX)as an anti-metastasis agent to treat breast cancer.CTCE-DTX could selfassemble to nanoparticles,targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy.Thus,the CTCE-DTX NPs achieved promising efficacy on inhibiting both bonespecific metastasis and lung metastasis of triple-negative breast cancer.Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.

Immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity

Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.

Self-assembly of DNA molecules at bio-interfaces and their emerging applications for biomedicines

Interfacial assembly has been intensively investigated in fabricating biomaterials and nanodevices for various applications.Recently,due to the precise sequence programmability,unique molecular recognition ability,and good biocompatibility,deoxyribonucleic acid(DNA)has been explored as superior building blocks to assemble at bio-interface for manipulating biological entities.To the best of our knowledge,the advances in this area have not been systematically summarized.To provide an overview of the area,in this review,the recently developed DNA assembly strategies on bio-interfaces were well summarized,and their representative works are exampled to illustrate how to rationally and elaborately design DNA molecules to realize functional integration and emerging of novel biological functionalities with high controllability and programmability.Furthermore,the biomedical applications of DNA assembly at bio-interface are categorially elaborated.The fascinating and unique advantages of DNA assembly systems are fully discussed in the exemplified applications to show the distinguished perspective of DNA in the future development.At the end of this review,the current limitations and challenges in applications and potential improvement strategies for DNA assembly at bio-interface are fully discussed.The future development direction is deliberated.We envision that this review will help scientists in the interdisciplinary fields gain a more comprehensive understanding of the DNA assembly at bio-interface,and therefore jointly promote the advances in this field.

Nanotechnology-based combinational strategies toward the regulation of myofibroblasts and diseased microenvironment in liver fibrosis and hepatic carcinoma

Liver fibrosis and hepatic carcinoma(HCC)pose a huge challenge worldwide due to the lack of effective treatment options for end-stage liver diseases.According to their functions and roles,hepatic myofibroblasts mainly include nontumoral fibroblasts(mainly activated hepatic stellate cells(HSCs)),which are involved in the wound-healing process of liver fibrosis,and cancer-associated fibroblasts(CAFs)in hepatic HCC.HSCs play a significant role in regulating extracellular matrix(ECM)deposition in progressive liver fibrosis.CAFs can be derived from activated HSCs and differentiate into ECM-producing myofibroblasts.Moreover,growing evidence shows that CAFs are the primary regulators of the HCC microenvironment,releasing growth factors and cytokines and suppressing the antitumor immune response.Combined therapeutic strategies show reduced drug resistance and side effects.Nanotechnology-based combined strategies aim to improve the delivery efficiency of various therapeutic agents with reduced toxicity via multiple mechanisms.In this review,we will discuss recent developments in combinational strategies based on nanotechnology that regulate myofibroblasts and the diseased microenvironment for liver fibrosis and HCC treatment.We will also identify the major challenges that the field is facing and offer some insights for future drug discovery.

Intelligent nanomaterials for cancer therapy:recent progresses and future possibilities

Intelligent nanomedicine is currently one of the most active frontiers in cancer therapy development.Empowered by the recent progresses of nanobiotechnology,a new generation of multifunctional nanotherapeutics and imaging platforms has remarkably improved our capability to cope with the highly heterogeneous and complicated na-ture of cancer.With rationally designed multifunctionality and programmable assembly of functional subunits,the in vivo behaviors of intelligent nanosystems have become increasingly tunable,making them more efficient in performing sophisticated actions in physiological and path-ological microenvironments.In recent years,intelligent nanomaterial-based theranostic platforms have showed great potential in tumor-targeted delivery,biological barrier circumvention,multi-responsive tumor sensing and drug release,as well as convergence with precise medication approaches such as personalized tumor vaccines.On the other hand,the increasing system complexity of anti-cancer nanomedicines also pose significant challenges in charac-terization,monitoring and clinical use,requesting a more comprehensive and dynamic understanding of nano-bio interactions.This review aims to briefly summarize the recent progresses achieved by intelligent nanomaterials in tumor-targeted drug delivery,tumor immunotherapy and temporospatially specific tumor imaging,as well as impor-tant advances of our knowledge on their interaction with biological systems.In the perspective of clinical translation,we have further discussed the major possibilities provided by disease-oriented development of anti-cancer nano-materials,highlighting the critical importance clinically-oriented system design.

A special issue for the 20^(th) anniversary of National Center for Nanoscience and Technology

National Center for Nanoscience and Technology(NCNST),China,established in December 2003,is co-founded by the Chinese Academy of Sciences(CAS)and the Ministry of Education as an institution dedicated to fundamental and applied researches in the field of nanoscience and technology,especially those with important potential applications.NCNST is operated under the supervision of the Governing Board and aims to become a world-class research center,as well as public technological platform and young talents training center in the field,and to act as an important bridge for international academic exchange and collaboration.The NCNST currently has three CAS Key Laboratories:the CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety,the CAS Key Laboratory for Standardization and Measurement for Nanotechnology and the CAS Key Laboratory for Nanosystem and Hierarchical Fabrication.In 2020,the CAS Key Laboratory of Nanophotonic Materials and Devices started construction.Besides,there are Division of Nanotechnology Development,Nanofabrication Laboratory,Intelligent Nanosensing Laboratory and Theoretical Laboratory.

Engineering Multifunctional Thylakoid as an Oxygen Self-Supplying Photosensitizer for Esophageal Squamous Cell Carcinoma-Targeted Photodynamic Therapy

Photodynamic therapy(PDT)has emerged as an alternative treatment strategy for esophageal squamous cell carcinoma(ESCC).However,the clinical therapeutic efficiency of PDT is severely limited by poorly targeted photosensitizer delivery,insufficient oxygen supply,and neutralization by excessive glutathione(GSH)in tumor tissue.Herein,an engineered multifunctional thylakoid nanostructure,TMEM@PLGA@GA(abbreviated as TEPG),composed of a thylakoid membrane(TM)and ESCC cell membrane(EM)-fused biomembrane(TM-EM)shell and gambogic acid(GA)-loaded poly(lactic-co-glycolic acid)nanocore,was designed for enhanced PDT for ESCC.When fused with EM,TM-EM exhibits a tumor targeting advantage due to the homologous affinity of tumor membrane camouflage.The catalase present on TM-EM catalytically decomposes endogenous hydrogen peroxide into oxygen to alleviate hypoxia in the tumor tissue.Moreover,when TEPG was selectively internalized by ESCC cells,GA was released to consume the excessive intracellular GSH.Under infrared irradiation,the PDT effects were enhanced by the self-oxygen supply and GSH scavenging ability provided by TEPG.An in vivo study showed that TEPG effectively induced ESCC tumor cell apoptosis and greatly inhibited the growth of ESCC tumors under infrared irradiation.This study constructed an engineered multifunctional thylakoid-based nanomedicine as an integrated solution to enhance PDT for ESCC.

针对肿瘤微环境精确设计的智能抗肿瘤纳米药物

肿瘤微环境调控概念的兴起极大推进了智能纳米药物的发展.作为治疗或递药靶点,基质和血管等微环境成分在基因层面上较肿瘤细胞更稳定,并且提供了在递药过程中绕过部分生物屏障的可能.我们的研究表明,充分利用纳米材料的固有优势和功能化潜力,针对肿瘤微环境精确设计纳米药物,对于开发和实现新的纳米抗肿瘤策略至关重要.例如,利用高精度自组装的核酸纳米机器,能够实现强效凝血分子在血液循环中的安全递送;利用多重释药的纳米结构局域性清除肿瘤相关血小板,可提高纳米药物穿透肿瘤血管内皮屏障的效率等.基于以上学术思想,近年来,我们系统研究了针对不同微环境成分或病理状态的靶向调控策略,利用智能纳米药物实现了包括肿瘤血管特异性栓塞、肿瘤基质微环境重塑、肿瘤血管通透性增强等创新性微环境调控方案.本文综述了其中的代表性进展,讨论了相关智能纳米体系在肿瘤微环境调控中的潜力和局限,并分析了智能抗肿瘤纳米药物的未来发展方向.

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

Co-delivery of doxorubicin and quercetin via mPEG-PLGA copolymer assembly for synergistic anti-tumor efficacy and reducing cardio-toxicity

橡黄素(Que ) 是自然多功能的 bioflavonoid，并且为减少不利副作用并且提高化学疗法的药的反肿瘤功效显示出大潜力。然而，它的临床的申请在生理的系统由于很低的溶解度和结构的不稳定性被限制。此处，我们共同交付由开发 amphiphilic 聚合物包括的 biocompatible nanocarrier 的恐水病的橡黄素和吸水的 doxorubicin (纪录影片) ， methoxy poly (乙烯乙二醇) 并且 poly (D， L-lactide-co-glycolide ) 分别地。反肿瘤和这个系统的预防功效被评估在细胞并且动物模型。我们说明的调查结果 Dox-Que nanoparticulate 明确的表达保护了正常脉管的 endothelial 房间免受免费的任何一个或 nanoparticulate 的伤害导致 doxorubicin 的 cytotoxicity 和增加的癌症房间死亡。与免费 doxorubicin 和它的 nanoformulation 相比，用我们的 nanosystem 的橡黄素和 doxorubicin 的合作交货 synergistically 禁止了肿瘤生长，当在浆液维持心脏的功能指示物的正常层次并且在心织物恢复组织病理学说的损坏时。这研究为提高反癌症药功效并且减少 nanoparticulate 表明有希望的策略正常纸巾上的导致化疗的毒性。

Attenuation ofβ-Amyloid Toxicity In Vitro and In Vivo by Accelerated Aggregation

Accumulation and aggregation of β-amyloid（Aβ） peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer＇s disease. The self-assembled Aβ molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Aβ toxicity is to facilitate the conversion of Aβ intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Aβ by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Aβ monomers, accompanying reduced Aβ cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Aβ oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Aβ aggregation-promotion effect can potentially be useful for developing strategies to reduce Aβ toxicity.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer

Reversal of cancer drug resistance remains a critical challenge in chemotherapy.Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer.To overcome the intrinsic limitations in conventional mitochondrial targeting strategies,we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin(DOX)resistance in lung cancer.Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors.As a consequence,thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice.This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

Personalized cancer vaccines from bacteria-derived outer membrane vesicles with antibody-mediated persistent uptake by dendritic cells

Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen,thus efficiently facilitating antitumor adaptive immunity.Bacteria-derived outer membrane vesicles(OMVs)are an excellent candidate due to their abundance of pathogen associated molecular patterns.However,during the uptake of OMVs by dendritic cells(DCs),the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage,a phenomenon we refer to as“maturation-induced uptake obstruction"(MUO).Herein we decorated OMV with the DC-targeting aDEC205 antibody(OMV-DEC),which endowed the nanovaccine with an uptake mechanism termed as 4<not restricted to maturation via antibody modifying”(Normandy),thereby overcoming the MUO phenomenon.We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display.In summary,this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines,and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design.

Analytical methods for nano-bio interface interactions

Knowledge on the interactions between engineered nanomaterials(ENMs) and biological systems is critical both for the assessment of biological effects of ENMs and for the rational design of ENM-based products. However, probing the events that occur at the nano-bio interface remains extremely challenging due to their complex and dynamic nature. So far, the understanding of mechanisms underlying nano-bio interactions has been mainly limited by the lack of proper analytical techniques with sufficient sensitivity, selectivity and resolution for characterization of nano-bio interface events. Moreover, many classic bioanalytical methods are not suitable for direct measurement of nano-bio interface interactions. These have made establishing analytical methodologies for systematic and comprehensive study of nano-bio interface one of the most focused areas in nanobiology. In this review we have discussed some representative developments regarding analytical techniques for nano-bio interface characterization, including the improvements of traditional methods and the emergence of powerful new technologies. These developments have allowed ultrasensitive, real-time analysis of interactions between ENMs and biomolecules, transformations of ENMs in biological environment, and impacts of ENMs on living systems on molecular or cellular level.

Molecularly engineered tumor acidity-responsive plant toxin gelonin for safe and efficient cancer therapy

Due to the unsatisfactory therapeutic efficacy and inexorable side effects of small molecule antineoplastic agents,extensive efforts have been devoted to the development of more potent macromolecular agents with highspecificity.Gelonin is a plant-derived protein toxin that exhibits robust antitumor effect via inactivating ribosomesand inhibiting protein synthesis.Nonetheless,its poor internalization ability to tumor cells has compromisedthe therapeutic promise of gelonin.In this study,a tumor acidity-responsive intracellular protein deliverysystem-functional gelonin(Trx-pHLIP-Gelonin,TpG)composed of a thioredoxin(Trx)tag,a pH low insertionpeptide(pHLIP)and gelonin,was designed and obtained by genetic recombination technique for the first time.TpG could effectively enter into tumor cells under weakly acidic conditions and markedly suppress tumor cellproliferation via triggering cell apoptosis and inhibiting protein synthesis.Most importantly,treatment byintravenous injection into subcutaneous SKOV3 solid tumors in a mouse model showed that TpG was much moreeffective than gelonin in curtailing tumor growth rates with negligible toxicity.Collectively,our present worksuggests that the tumor acidity-targeted delivery manner endowed by pHLIP offers a new avenue for efficientdelivery of other bioactive substances to acidic diseased tissues.

Molecularly engineered truncated tissue factor with therapeutic aptamers for tumor-targeted delivery and vascular infarction

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy.Among vascular coagulation agents,the extracellular domain of coagulation-inducing protein tissue factor,truncated tissue factor(tTF),is the most widely used.Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation,free tTF cannot be used for cancer treatment on its own but must be combined with other moieties.We here developed a novel,tumor-specific tTF delivery system through coupling tTF with the DNA aptamer,AS1411,which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells.Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors,thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects.This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

Nanotechnological strategies for prostate cancer imaging and diagnosis

The high incidence rates and complicated subtypes of prostate cancer(PCa)call for the demand of the precise diagnostic and therapeutic strategies.Current clinical imaging techniques,such as MRI,CT,and ultrasonography are difficult to accurately detect the early-stage tumor lesions,and biochemical assays or biopsies are invasive and cannot provide sufficient information for the PCa staging and classification.Nanotechnology has the potential to improve the accuracy of current diagnosis strategies by targeting specific PCa biomarkers and/or integrating multiple imaging modes.In this review,we briefly introduce current clinical PCa imaging strategies and their major limitations,and highlight representative works on nanoparticle-mediated multimode imaging strategies.We also discuss the challenges of nanotechnology-based PCa diagnosis,and come up with suggestions and perspectives.