2024

33.Regulatory T Cells Nanoextinguisher to Manipulate Multiple Immune Evasion for Immunotherapy

ACS Nano DOI: 10.1021/acsnano.4c04663

Caiyan Zhao , Changrong Wang  , Rujie Wang  , Wenbo Shan , Weipeng Wang  , Hongzhang Deng

Abstract

   Regulatory T cells (Treg) play key roles in inhibiting effective antitumor immunity. However, therapeutic Treg depletion fails to consistently enhance immune responses due to the emergence of a wave of peripherally converted Treg cells postdepletion, along with undesired off-target side effects. Here, we report a nanoextinguisher decorated with functional peptides via tumor microenvironment responsive linkers to selectively block Treg function and maintain Treg levels rather than deplete them. The nanoextinguisher specifically neutralizes TGF-β to inhibit the recruitment of Treg cells and the conversion of naive T cells into Treg cells, thus promoting antitumor immunity. Moreover, the nanoextinguisher can alleviate tumor resistance to immunogenic photodynamic therapy, vaccination therapy, and checkpoint inhibition. The nanoextinguisher showed 30-fold potentiation in antitumor effect compared to standalone photodynamic therapy or vaccination therapy. Overall, utilizing a nanoextinguisher to inhibit Treg function without triggering reconversion represents a generalizable method to reverse immune evasion, yielding antitumor efficacy.

32.Fusogenic Lipid Nanovesicle for Biomacromolecular Delivery

       Nano Lett. 2024  10.1021/acs.nanolett.4c01709

           Caiyan Zhao, Changrong Wang, Wenbo Shan, Weipeng Wang, and Hongzhang Deng*

Abstract

     Although biomacromolecules are promising cytosolic drugs which have attracted tremendous attention, the major obstacles were the cellular membrane hindering the entrance and the endosome entrapment inducing biomacromolecule degradation. How to avoid those limitations to realize directly cytosolic delivery was still a challenge. Here, we prepared oligoarginine modified lipid to assemble a nanovesicle for biomacromolecules delivery, including mRNA (mRNA) and proteins which could be directly delivered into the cytoplasm of dendritic cells through subendocytosis-mediated membrane fusion. We named this membrane fusion lipid nanovesicle as MF-LNV. The mRNA loaded MF-LNV as nanovaccines showed efficient antigen expression to elicit robust immuno responses for cancer therapy. What’s more, the antigen protein loaded MF-LNV as nanovaccines elicits much stronger CD8+ T cell specific responses than lipid nanoparticles through normal uptake pathways. This MF-LNV represented a refreshing strategy for intracellular delivery of the biomacromolecule.

31.Nanomedicines for an Enhanced Immunogenic Cell Death-Based In Situ Cancer Vaccination Response

        Accounts of Chemical Research 2024, 57, 6, 905–918 10.1021/acs.accounts.3c00771

Caiyan Zhao, Changrong Wang, Wenbo Shan, Zhongliang Wang*, Xiaoyuan Chen*, and Hongzhang Deng*

Abstract

     Cancer vaccines have shown tremendous potential in preventing and treating cancer by providing immunogenic antigens to initiate specific tumor immune responses. An in situ vaccine prepared from an autologous tumor can mobilize a patient’s own tumor cell lysate as a reservoir of specific antigens, thus triggering a broad immune response and diverse antitumor immunity in an individually tailored manner. Its efficacy is much better than that of conventional vaccines with a limited number of epitopes. Several conventional therapies, including radiotherapy (RT), chemotherapeutics, photodynamic therapy (PDT), and photothermal therapy (PTT) can activate an anticancer in situ vaccine response by inducing immunogenic cell death (ICD), triggering the exposure of tumor-associated antigens (TAAs), cancerous testis antigens, neoantigens, and danger-associated molecular patterns (DAMPs) with low cost. However, the immunogenicity of dying tumor cells is low, making released antigens and DAMPs insufficient to initiate a robust immune response against malignant cancer. Moreover, the immunosuppressive tumor microenvironment (TME) severely hinders the infiltration and sensitization of effector immune cells, causing tolerogenic immunological effects.

     Herein, we mainly focus on the research in developing nanoplatforms to surmount the major challenges met by ICD-based in situ vaccines. We first summarized a variety of nanotechnologies that enable enhanced immunogenicity of dying cancer cells by enhancing antigenicity and adjuvanticity. The robust antigenicity was obtained via regulating the tumor cells death mode or the dying state to amplify the recognition of tumor debris by professional antigen-presenting cells (APCs). The adjuvanticity was potentiated by raising the level or intensifying the activity of endogenous adjuvants or promoting the intelligent delivery of exogenous immunostimulants to activate immune cell recruitment and promote antigen presentation. Additionally, versatile approaches to reverse immunosuppressive TME to boost the in situ tumor vaccination response are also highlighted in detail. On one hand, by modulating the cell metabolism in TME, the expansion and activity of effector versus immunosuppressive cells can be optimized to improve the efficiency of in situ vaccines. On the other hand, regulating cellular components in TME, such as reversing adverse immune cell phenotypes or inhibiting the activity of interstitial cells, can also significantly enhance the ICD-based antitumor immunotherapy effect. Finally, our viewpoint on the future challenges and opportunities in this hopeful area is presented. We expect that this Account can offer much more insight into the design, planning, and development of cutting-edge in situ tumor vaccine platforms, promoting more attention and academic–industry collaborations, accelerating the advanced progress of in situ tumor vaccine-based immunotherapy in the clinic.

2023

    30.Biomimetic noncationic lipid nanoparticles for mRNA delivery

PNAS, 2023,120, e2311276120.  10.1073/pnas.2311276120

Changrong Wang, Caiyan Zhao, Weipeng Wang, Xiaoqing Liu and Hongzhang Deng,

Abstract

Although the tremendous progress has been made for mRNA delivery based on classical cationic carriers, the excess cationic charge density of lipids was necessary to compress mRNA through electrostatic interaction, and with it comes inevitably adverse events including the highly inflammatory and cytotoxic effects. How to develop the disruptive technologies to overcome cationic nature of lipids remains a major challenge for safe and efficient mRNA delivery. Here, we prepared noncationic thiourea lipids nanoparticles (NC- TNP) to compress mRNA by strong hydrogen bonds interaction between thiourea groups of NC- TNP and the phosphate groups of mRNA, abandoning the hidebound and traditional electrostatic forceto construct mRNA- cationic lipids formulation. NC- TNP was a delivery system for mRNA with simple, convenient, and repeatable preparation technology and showednegligible inflammatory and cytotoxicity side effects. Furthermore, we found that NC- TNP could escape the recycling pathway to inhibit the egress of internalized nanoparticles fromthe intracellular compartment to the extracellular milieu which was a common fact in mRNA- LNP (lipid nanoparticles) formulation. Therefore, NC- TNP- encapsulated mRNA showed higher gene transfection efficiency in vitro and in vivo than mRNA- LNP formulation. Unexpectedly, NC- TNP showed spleen targeting delivery ability with higher accumulation ratio (spleen/liver), compared with traditional LNP. Spleen- targeting NC- TNP with mRNA exhibited high mRNA- encoded antigen expression in spleen and elicited robust immune responses. Overall, our work establishes a proof of concept for the constructionof a noncationic system for mRNA delivery with good inflammatory safety profiles, highgene transfection efficiency, and spleen- targeting delivery to induce permanent and robust humoral and cell- mediated immunity for disease treatments.

29.mRNA Cancer Vaccines: Construction and Boosting Strategies

ACS Nano,2023,17, 20, 19550–19580. 10.1021/acsnano.3c05635

Xiaoqing Liu, Pei Huang, Rusen Yang, Hongzhang Deng.

Abstract

In late 2020, the U.S. Food and Drug Administration (FDA) approved a lipid-based mRNA vaccine for the prevention of COVID-19, which has pushed this field to be more closely studied and motivated researchers to delve deeper into mRNA therapeutics. To date, the research on mRNA cancer vaccines has been developed rapidly, and substantial hopeful therapeutic results have been achieved against various solid tumors in clinical trials. In this review, we first introduce three main components of mRNA cancer vaccines, including mRNA antigens, adjuvants, and delivery vectors. Engineering these components can optimize the therapeutic effects of mRNA cancer vaccines. For instance, appropriate modification of mRNA structure can alleviate the poor stability and innate immunogenicity of mRNA, and the use of mRNA delivery vectors can address the issues of low delivery efficiency in vivo. Second, we emphatically discuss some strategies to further improve the efficacy of mRNA cancer vaccines, namely modulating the immunosuppressive tumor environment, optimizing administration routes, achieving targeting delivery to intended tissues or organs, and employing combination therapy. These strategies can strengthen the tumor inhibitory ability of mRNA cancer vaccines and increase the possibility of tumor elimination. Finally, we point out some challenges in the clinical practice of mRNA cancer vaccines and offer our perspectives on future developments in this rapidly evolving field. It is anticipated that mRNA cancer vaccines will be rapidly developed for clinical cancer therapy in the near future.

28.Surface Engineering of Nanoparticles toward Cancer Theranostics

Accounts of Chemical Research 2023, 56, 1766-1779. 10.1021/acs.accounts.3c00122

Pei Huang, Changrong Wang, Hongzhang Deng,Yongfeng Zhou,  Xiaoyuan Chen

Abstract

Development of multifunctional nanoparticles (NPs) with desired properties is a significant topic in the field of nanotechnology and has been anticipated to revolutionize cancer diagnosis and treatment modalities. The surface character is one of the most important parameters of NPs that can directly affect their in vivo fate, bioavailability, and final theranostic outcomes and thus should be carefully tuned to maximize the diagnosis and treatment effects while minimizing unwanted side effects. Surface engineered NPs have utilized various surface functionality types and approaches to meet the requirements of cancer therapy and imaging. Despite the various strategies, these surface modifications generally serve similar purposes, namely, introducing therapeutic/imaging modules, improving stability and circulation, enhancing targeting ability, and achieving controlled functions. These surface engineered NPs hence could be applied in various cancer diagnosis and treatment scenarios and continuously contribute to the clinical translation of the next-generation NP-based platforms toward cancer theranostics.

In this Account, we present recent advances and research efforts on the development of NP surface engineering toward cancer theranostics. First, we summarize the general strategies for NP surface engineering. Various types of surface functionalities have been applied including inorganic material-based functionality, organic material-based functionality like small molecules, polymers, nucleic acids, peptides, proteins, carbohydrates, antibodies, etc., and biomembrane-based functionality. These surface modifications can be realized by prefabrication or postfabrication functionalization, driven by covalent conjugations or noncovalent interactions. Second, we highlight the general aims of these different NPs surface functionalities. Different therapeutic and diagnostic modules, such as nanozymes, antibodies, and imaging contrast agents, have been modified on the surface of NPs to achieve theranostic function. Surface modification also can improve stability and circulation of NPs by protecting the NPs from immune recognition and clearance. In addition, to achieve targeted therapy and imaging, various targeting moieties have been attached on the NP surface to enhance active targeting ability to tissues or cells of interest. Furthermore, the NP surfaces can be tailored to achieve controlled functions which only respond to specific internal (e.g., pH, thermal, redox, enzyme, hypoxia) or external (e.g., light, ultrasound) triggers at the precise action sites. Finally, we present our perspective on the remaining challenges and future developments in this significant and rapidly evolving field. We hope this Account can offer an insightful overlook on the recent progress and an illuminating prospect on the advanced strategies, promoting more attention in this area and adoption by more scientists in various research fields, accelerating the development of NP surface engineering with a solid foundation and broad cancer theranostics applications.

27.Gas-assisted phototherapy for cancer treatment

journal of Controlled Release 2023, 360, 564-577.10.1016/j.jconrel.2023.07.015

Jun Zhou , Chen Cao , Xinlu Zhang , Xu Zhang , Jiansen Li , Hongzhang Deng , Sheng Wang 

Abstract

Phototherapies, mainly including photodynamic and photothermal therapy, have made considerable strides in the field of cancer treatment. With the aid of phototherapeutic agents, reactive oxygen species (ROS) or heat are generated under light irradiation to selectively damage cancer cells. However, sole-modality phototherapy faces certain drawbacks, such as limited penetration of phototherapeutic agents into tumor tissues, inefficient ROS generation due to hypoxia, treatment-induced inflammation and resistance of tumor to treatment (e.g., high levels of antioxidants, expression of heat shock protein). Gas therapy, an emerging therapy approach that damages cancer cells by improving the level of certain gas at the tumor site, shows potential to overcome the challenges associated with phototherapies. In addition, with the rapid development of nanotechnology, gas-assisted phototherapy based on nanomedicines has emerged as a promising strategy to enhance the treatment efficacy. This review summarizes recent advances in gas-assisted phototherapy and discusses the prospects and challenges of this strategy in cancer phototherapy.

26.Noncovalent co-assembly of aminoglycoside antibiotics@tannic acid nanoparticles for off-the-shelf treatment of pulmonary and cutaneous infections. 

Chemical Engineering Journal 2023, 474, 145703.10.1016/j.cej.2023.145703

Guang Yang, Changrong Wang*, Yaping Wang, Xiaoqing Liu, Ye Zhang, Ming Xu, Hongzhang Deng

Abstract

Antibiotics still serve as the first choice for combating bacterial infections, whereas the therapeutic efficiency of antibiotics needs to be further augmented. Here, we report the spontaneous, generalized noncovalent co-assembly of aminoglycoside antibiotics (AGs) with tannic acid (TA) through electrostatic and hydrogen-bond interactions to form nanoparticles in water as off-the-shelf antibacterial agents. Specially, tobramycin@TA nanoparticles (Tob@TA NPs) elicited superior sterilization efficacy over native Tob against both Gram-positive and Gram-negative bacterial strains by enhancing the attachment onto the bacteria surface and the production of intracellular reactive oxygen species (ROS), disturbing membrane potential and promoting the leakage of bioactive substance such as DNA. Importantly, Tob@TA NPs also showed enhanced antibacterial efficacy against Tob-resistant Pseudomonas aeruginosa (P. aeruginosa). In P. aeruginosa-induced acute pneumonia model, the administration of Tob@TA NPs could eliminate bacterial infection and reduce inflammation. Furthermore, co-assembled Tob@TA NPs loaded in adhesive gelatin hydrogel dressing significantly accelerated the healing of P. aeruginosa-infected skin wound by effectively eradicating bacteria, decreasing inflammation and improving angiogenesis. Taking together, our findings provide a facile, simple and effective methodology to construct ready-to-use aminoglycoside antibiotics@TA NPs for the eradication of bacterial infection in clinic.

25.Cellular Trafficking of Nanotechnology-Mediated mRNA Delivery.

Advaned Materials 2023, 10.1002/adma.202307822.

Pei Huang, Hongzhang Deng, Changrong Wang, Yongfeng Zhou, Xiaoyuan Chen

Abstract

Messenger RNA (mRNA)-based therapy has emerged as a powerful, safe, and rapidly scalable therapeutic approach that involves technologies for both mRNA itself and the delivery vehicle. Although there are some unique challenges for different applications of mRNA therapy, a common challenge for all mRNA therapeutics is the transport of mRNA into the target cell cytoplasm for sufficient protein expression. This review is focused on the behaviors at the cellular level of nanotechnology-mediated mRNA delivery systems, which have not been comprehensively reviewed yet. First, the four main therapeutic applications of mRNA are introduced, including immunotherapy, protein replacement therapy, genome editing, and cellular reprogramming. Second, common types of mRNA cargos and mRNA delivery systems are summarized. Third, strategies to enhance mRNA delivery efficiency during the cellular trafficking process are highlighted, including accumulation to the cell, internalization into the cell, endosomal escape, release of mRNA from the nanocarrier, and translation of mRNA into protein. Finally, the challenges and opportunities for the development of nanotechnology-mediated mRNA delivery systems are presented. This review can provide new insights into the future fabrication of mRNA nanocarriers with desirable cellular trafficking performance.

24.Regulation of TiO2 @PVDF piezoelectric nanofiber membranes on osteogenic differentiation of mesenchymal stem cells.

Nano Energy 2023, 115, 108742.10.1016/j.nanoen.2023.108742

Jing Liu, Yaya Cheng, Haoyu Wang, Dingyi Yang, Cunshun Liu, Weixin Dou, Xue Jiang, Hongzhang Deng, Rusen Yang

Abstract

Bioactive piezoelectric materials with similar properties as natural bone tissue with piezoelectricity have been explored for bone repair. Polyvinylidene fluoride (PVDF) is among the most studied piezoelectric polymers and has been manifested to promote osteogenic differentiation. Unfortunately, in the practical application of bone repair, bioactive materials as implants have faced poor electrical signal stability and poor modulation of bone regeneration, which have seriously hindered their further development. Here, we fabricated a composite piezoelectric fibrous membrane with titanium dioxide (TiO2) nanoparticles and PVDF (TiO2 @PVDF) for cellular osteogenic differentiation. The expression quantity of the gene osteocalcin (OCN) with the piezoelectric fibrous membrane was 49 times and 6 times higher than the expression quantity of OCN with the control group and with the pure polyvinylidene fluoride (PVDF), respectively. Moreover, the membrane with 0.3 wt% TiO2 (P-0.3TN) generated high surface potential and significantly promoted cell adhesion and proliferation through electromechanical stimulation early in osteogenic differentiation. Alkaline phosphatase (ALP) activity was increased up to 2-fold by stimulation of electrical and mechanical signals through piezoelectric fibers, effectively inducing osteogenic differentiation at the early stage. The proposed mechanism of regulating osteogenic differentiation behavior by the surface potential of TiO2 @PVDF piezoelectric fiber composite membrane provides guidance for designing electroactive materials to promote osteogenic differentiation and bone regeneration and remodeling.

                   

23.X-ray guided in situ genetic engineering of macrophage for sustained cancer immunotherapy. 

Advanced Materials 2023, 35, 2208059. 10.1002/adma.202208059

Caiyan Zhao, Yaya Cheng, Pei Huang, Changrong Wang, Weipeng Wang, Mengjiao Wang, Hongzhang Deng

Abstract

Effective repolarization of macrophages has emerged as a promising approach for anticancer therapy. However, there are very few studies on the effect of reprogramming macrophages from M2 phenotype to M1 phenotype without reconversion while maintaining an activated M1 phenotype. Moreover, these immunomodulatory methods have serious drawbacks due to the activation of normal monocytic cells. Therefore, it remains a challenge to selectively reprogram tumor-associated macrophages (TAMs) without systemic toxicities. Here, X-ray-guided and triggered remote control of a CRISPR/Cas9 genome editing system (X-CC9) that exclusively activates therapeutic agents at tumor sites is established. Under X-ray irradiation, X-CC9 selectively enhances M2-to-M1 repolarization within the tumor microenvironment, and significantly improves antitumor efficacy with robust immune responses in two animal models. This strategy provides an ideal method for improving the safety of macrophage polarization and may constitute a promising immunotherapy strategy.

        

                                   

22.An Integrated polymeric mRNA vaccine without inflammation side‐effects for cellular immunity mediated cancer therapy. 

Advanced Materials 2023, 35, 2207471.10.1002/adma.202207471

Pei Huang, Lingsheng Jiang, Hui Pan, Lingwen Ding, Bo Zhou, Mengyao Zhao, Jianhua Zou, Benhao Li, Meiwei Qi, Hongzhang Deng, Yongfeng Zhou, Xiaoyuan Chen

Abstract

Among the few available mRNA delivery vehicles, lipid nanoparticles (LNPs) are the most clinically advanced but they require cumbersome four components and suffer from inflammation-related side effects that should be minimized for safety. Yet, a certain level of proinflammatory responses and innate immune activation are required to evoke T-cell immunity for mRNA cancer vaccination. To address these issues and develop potent yet low-inflammatory mRNA cancer vaccine vectors, a series of alternating copolymers “PHTA” featured with ortho-hydroxy tertiary amine (HTA) repeating units for mRNA delivery is synthesized, which can play triple roles of condensing mRNA, enhancing the polymeric nanoparticle (PNP) stability, and prolonging circulation time. Unlike LNPs exhibiting high levels of inflammation, the PHTA-based PNPs show negligible inflammatory side effects in vivo. Importantly, the top candidate PHTA-C18 enables successful mRNA cancer vaccine delivery in vivo and leads to a robust CD8+ T cell mediated antitumor cellular immunity. Such PHTA-based integrated PNP provides a potential approach for establishing mRNA cancer vaccines with good inflammatory safety profiles.

        

2022

21.Harnessing immune response using reactive oxygen species-generating/eliminating inorganic biomaterials for disease treatment.

Advanced Drug Delivery Reviews 2022, 188, 114456.10.1016/j.addr.2022.114456

 Caiyan Zhao, Hongzhang Deng, Xiaoyuan Chen

Abstract

With the increasing understanding of various biological functions mediated by reactive oxygen species (ROS) in the immune system, a number of studies have been designed to develop ROS-generating/eliminating strategies to selectively modulate immunogenicity for disease treatment. These strategies potentially exploit ROS-modulating inorganic biomaterials to harness host immunity to maximize the therapeutic potency by eliciting a favorable immune response. Inorganic biomaterial-guided in vivo ROS scavenging can exhibit several effects to: i) reduce the secretion of pro-inflammatory factors, ii) induce the phenotypic transition of macrophages from inflammatory M1 to immunosuppressive M2 phase, iii) minimize the recruitment and infiltration of immune cells. and/or iv) suppress the activation of nuclear factor kappa-B (NF-κB) pathway. Inversely, ROS-generating inorganic biomaterials have been found to be capable of: i) inducing immunogenic cell death (ICD), ii) reprograming tumor-associated macrophages from M2 to M1 phenotypes, iii) activating inflammasomes to stimulate tumor immunogenicity, and/or iv) recruiting phagocytes for antimicrobial therapy. This review provides a systematic and up-to-date overview on the progress related to ROS-nanotechnology mediated immunomodulation. We highlight how the ROS-generating/eliminating inorganic biomaterials can converge with immunomodulation and ultimately elicit an effective immune response against inflammation, autoimmune diseases, and/or cancers. We expect that contents presented in this review will be beneficial for the future advancements of ROS-based nanotechnology and its potential applications in this evolving field.

              

20.The roles of polymers in mRNA delivery.

 Matter 2022, 5, 1670-1699. 10.1016/j.matt.2022.03.006

Pei Huang, Hongzhang Deng, Yongfeng Zhou, Xiaoyuan Chen

Abstract

• mRNA therapy, which possesses distinctive advantages over DNA and protein-based therapies, has immense potential for diverse applications, including mRNA vaccines, protein-replacement therapy, gene editing, and cell reprogramming. Nevertheless, successful mRNA therapy requires the production of stable mRNA with minimal immunogenicity and establishment of a safe and effective delivery system. Polymeric mRNA delivery vehicles have attracted great interest recently and developed quickly rendered by endless synthetic capability, versatile structure, and robust stability. In this review, firstly, we summarize the development of polymeric nanocarriers for mRNA delivery. Secondly, the approaches to enhance mRNA transfection efficiency are emphatically discussed, involving tuning the polymer structure, engineering the polymeric nanoparticles, and improving efficiency in the mRNA delivery process. Finally, conclusions and perspectives are proposed for mRNA therapy, especially regarding acceleration of their clinical translation. We believe that introduction of mRNA will lead to next-generation promising techniques for disease prevention and treatment in the near future.

        

19.Self-sufficient copper peroxide loaded pKa-tunable nanoparticles for lysosome-mediated chemodynamic therapy

Nano Today 2022, 2, 101337.10.1016/j.nantod.2021.101337

Hongzhang Deng, Zuo Yang, Xiaoyu Pang, Caiyan Zhao, Jie Tian, Zhongliang Wang, Xiaoyuan Chen

Abstract

Chemodynamic therapy (CDT) has recently gained much attention for Fenton chemistry-mediated cancer treatment, but the anti-tumor efficacy of CDT suffers from insufficient amount of endogenous H2O2 and inefficient decomposition of metal oxides to catalytic ions. Although tremendous progress has been made to increase the amount of H2O2 in the tumor region, the antitumor activity of CDT remains limited due to the suboptimal ionization to release enough amounts of catalytic ions for converting endogenous H2O2 to reactive oxygen species (e.g. highly toxic hydroxyl radical ·OH). Here, a series of nanoparticles with tunable acid dissociation constant (pKa) values from 5.2 to 6.2 were prepared to load H2O2 self-supplying copper peroxide, which can be used to trap copper peroxide in acidic lysosome to produce ample catalytic ions that convert self-supplied H2O2 into ·OH by a robust Fenton reaction. The highly reactive ·OH effectively permeate the lysosomal membrane through lipid peroxidation and thus kill tumor cells in a lysosome-mediated manner. Most importantly, the Fenton reaction is processed inside the lysosomal compartment, which avoids the cytoplasmic antioxidants such as glutathione (GSH) to scavenge ·OH. Overall, this work provides a new strategy to enhance CDT efficacy.

18.Nanomaterials targeting tumor associated macrophages for cancer immunotherapy.

Journal of Controlled Release 2022, 34, 272-284. 10.1016/j.jconrel.2021.11.028

Caiyan Zhao, Xiaoyu Pang, Zuo Yang, Sheng Wang, Hongzhang Deng, Xiaoyuan Chen

Abstract

Tumor-associated macrophages (TAMs) play an important role in regulating tumor growth, invasion and metastasis, and constitute approximately 50% of tumor mass. TAMs can exist in two different subtypes, M1-polarized phenotype (pro-inflammatory and immunostimulatory) and M2-polarized phenotype (immunosuppressive myeloid cells). M2 macrophages can suppress CD8+ T cells to support tumor survival. A number of biological strategies aimed at engineering macrophages to modulate the tumor immune microenvironment remain at the forefront of cancer research. Here, we review the different therapeutic strategies that have been developed based on nanotechnology to modulate macrophage functions, such as inhibition of macrophage recruitment to tumor, depletion of M2-polarized macrophages, reprograming of M2-polarized macrophages to M1-polarized macrophages, and blocking of the CD47-signal-regulatory protein alpha (CD47-SIRPα) pathway. Furthermore, we also discuss how to image TAMs with nanoparticles to unravel novel treatment options and observe their responses to the various therapies. Overall, macrophage-mediated immune modulation based on nanotechnology can be further investigated to be effectively developed as an immunoadjuvant therapy against different cancers.

      

17.Oxygen-evolving manganese ferrite nanovesicles for hypoxia-responsive drug delivery and enhanced cancer chemoimmunotherapy.

Advanced Functional Materials 2021,31, 2008078. 10.1002/adfm.202008078

Kuikun Yang, Guocan Yu, Rui Tian, Zijian Zhou, Bo Li, Hongzhang Deng*, Ling Li, Zhen Yang, Guofeng Zhang, Dahai Liu, Jianwen Wei, Ludan Yue, Ruibing Wang，Xiaoyuan Chen

Abstract

Immunological tolerance induced by the hypoxic tumor microenvironment has been a major challenge for current immune checkpoint blockade therapies. Here, a hypoxia-responsive drug delivery nanoplatform is reported to promote chemoimmunotherapy of cancer by overcoming the hypoxia-induced immunological tolerance of tumors. The nanovesicles are assembled from manganese ferrite nanoparticles (MFNs) grafted with hypoxia-responsive amphiphilic polymers as the membrane, with doxorubicin hydrochloride (Dox) loaded in the aqueous cavities. Under hypoxic conditions in tumors, the nanovesicles can rapidly dissociate into individual MFNs to release Dox and induce decomposition of tumor endogenous H2O2 for tumor hypoxia relief. As a result, the Dox-loaded nanovesicles display remarkable suppression of primary tumor growth in combination with αPD-L1-mediated checkpoint blockade therapy. Furthermore, the modulation of the hypoxic tumor microenvironment facilitates a long-lasting immunological memory effect to prevent tumor recurrence and metastasis. Therefore, this hypoxia-responsive nanoplatform presents a potential strategy for both local tumor treatment and long-term protection against tumor recurrence.

16.Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death.

 Nature Communications 2020, 11, 4951. 10.1038/s41467-020-18745-6

 Hongzhang Deng, Weijing Yang, Zijian Zhou, Rui Tian, Lisen Lin, Ying Ma, Jibin Song,  Xiaoyuan Chen

Abstract

Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.

15.Endoplasmic reticulum targeting to amplify immunogenic cell death for cancer immunotherapy.

 Nano Letters 2020, 20, 1929-1933. 10.1021/acs.nanolett.9b05210

 Hongzhang Deng, Zijian Zhou, Weijing Yang, Lisen Lin, Sheng Wang, Gang Niu, Jibin Song, Xiaoyuan Chen

Abstract

Immunogenic cell death (ICD) elicited by photodynamic therapy (PDT) is mediated through generation of reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress. However, the half-life of ROS is very short and the intracellular diffusion depth is limited, which impairs ER localization and thus limits ER stress induction. To solve the problem, we synthesized reduction-sensitive Ds-sP NPs (PEG-s-s-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] nanoparticles) loaded with an efficient ER-targeting photosensitizer TCPP-TER (4,4′,4″,4′″-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4-methylphenyl)sulfonamido)ethyl)benzamide). The resulting Ds-sP/TCPP-TER NPs could selectively accumulate in the ER and locally generate ROS under near-infrared (NIR) laser irradiation, which induced ER stress, amplified ICD, and activated immune cells, leading to augmented immunotherapy effect. This study presents a novel ICD amplifying, ER-targeting PDT strategy that can effectively eradicate primary tumors under NIR exposure, as well as distant tumors through an abscopal effect.

           

14.X-ray-controlled bilayer permeability of bionic nanocapsules stabilized by nucleobase pairing interactions for pulsatile drug delivery. 

Advanced Materials 2019, 31, 1903443.10.1002/adma.201903443

Hongzhang Deng, Lisen Lin, Sheng Wang, Guocan Yu, Zijian Zhou, Yijing Liu, Gang Liu, Jibin Song, Xiaoyuan Chen

Abstract

The targeted and sustained drug release from stimuli-responsive nanodelivery systems is limited by the irreversible and uncontrolled disruption of the currently used nanostructures. Bionic nanocapsules are designed by cross-linking polythymine and photoisomerized polyazobenzene (PETAzo) with adenine-modified ZnS (ZnS-A) nanoparticles (NPs) via nucleobase pairing. The ZnS-A NPs convert X-rays into UV radiation that isomerizes the azobenzene groups, which allows controlled diffusion of the active payloads across the bilayer membranes. In addition, the nucleobase pairing interactions between PETAzo and ZnS-A prevent drug leakage during their in vivo circulation, which not only enhances tumor accumulation but also maintains stability. These nanocapsules with tunable permeability show prolonged retention, remotely controlled drug release, enhanced targeted accumulation, and effective antitumor effects, indicating their potential as an anticancer drug delivery system.

           

13.Injectable Thermosensitive hydrogel systems based on functional PEG/PCL block polymer for local drug delivery.

Journal of Controlled Release 2019, 297, 60-70. 10.1016/j.jconrel.2019.01.026

Hongzhang Deng, Anjie Dong, Jibin Song, Xiaoyuan Chen

Abstract

Injectable in situ thermosensitive hydrogels have potential applications in tissue engineering and drug delivery. The hydrogel formulations exist as aqueous solutions at room temperature but rapidly solidify into gels at 37 °C in situ, making them highly suitable for administering drugs in a minimally invasive manner to the target organ(s). The hydrogel formed with nanoparticles assembled with amphiphilic polymer blocks of polyethyleneglycol (PEG) and biodegradable polycaprolactone (PCL) have been tested as platforms for targeted and sustained drug delivery, and have shown encouraging results. In this review, we summarize the influence of the molecular weight, PEG/PCL ratio and functional structure of hydrophobic PCL blocks on the critical gelation temperature, gelling behavior and drug release kinetics of the hydrogels. The current studies on the biomedical applications of thermosensitive PEG/PCL hydrogels have also been discussed.

12.Rational Design of Nanoparticles to Overcome Poor Tumor Penetration and Hypoxia-Induced Chemotherapy Resistance: Combination of Optimizing Size and Self-Inducing High Level of Reactive Oxygen Species

ACS Applied Materials & Interfaces 2019, 11, 31743-31754. 10.1021/acsami.9b12129

Liandong Deng, Zujian Feng, Hongzhang Deng, Yujia Jiang, Kun Song, Yongli Shi, Shuangqing Liu, Jianhua Zhang, Suping Bai, Zhihai Qin, Anjie Dong

Abstract

One tough question induced by the hypoxia in cancer tissue is resistance to anticancer drugs basing on the reactive oxygen species (ROS) mechanism. Furthermore, the hypoxic regions locate in the center of tumor where tumor cells are easily residual and survival due to the poor drug-delivery efficiency even with nanocarriers. In this paper, these problems were well addressed through the rational combination of the enhanced penetration, self-inducing high level of intracellular ROS, and synchronously pH-sensitive drug release, realized by a simple structural and accessible copolymer, poly(poly(ethylene glycol) methyl ether methacrylate-co-(2-methylpropenoic acid-glycerol-cinnamaldehyde)) (PgEMC). For one thing, PgEMC could self-assemble into stable nanoparticles with PEG shell and optimizing diameters of 60 nm to simultaneously facilitate long blood circulation and deep tumor penetration. Second, cinnamylaldehyde moieties could detach from PgEMC NPs in intracellular acidic environment and trigger high level of ROS to allay the doxorubicin (DOX) resistance induced by hypoxia in solid malignancies. Furthermore, the DOX payload in PgEMC NPs could be synchronously released with the intracellular disassembly of PgEMC NPs due to the detaching of cinnamylaldehyde moieties. In 4T1 cells treated with PgEMC/DOX NPs, remarkable elevation of ROS level and enhanced DOX sensitivity in hypoxia environment were observed in in vitro studies. The results of tumor spheroid penetration indicated that 60 nm sized DOX-loaded PgEMC NPs (PgEMC60/DOX) could distribute into deep site of tumor at a high intensity. In vivo studies using a 4T1 breast tumor model, PgEMC60/DOX NPs, showed significant inhibition over 95.4% of the tumor growth. These results reveal that integrating optimizing size, self-inducing ROS, and pH-sensitive drug release into one small-sized nanoparticle can efficiently overcome the poor tumor penetration and hypoxia-induced chemotherapy resistance.

            

11.Modulating the rigidity of nanoparticles for tumor penetration. 

Chemical Communications 2018, 54, 3014-3017. 10.1039/c8cc00398j

Hongzhang Deng, Kun Song, Jianhua Zhang, Liandong Deng, Anjie Dong, Zhihai Qin

Abstract

How the rigidity of nanoparticles affects their penetration into tumors is unclear. Core–shell nanoparticles were prepared with amphipathic poly(ethylene glycol)-b-(poly ε-caprolactone-g-poly butyl acrylate) (PEG–(PCL-g-PBA)) so that the mechanical stiffness of their cores could be varied in order to test the relationship between their rigidity and penetration through tumors. The rigidity of the nanoparticles was adjusted by the changeable crystallinity of the core, which was altered by varying the ratio of ε-caprolactone and butyl acrylate.

                      

10.Reactive oxygen species-responsive polymeric nanoparticles for alleviating sepsis-induced acute liver injury in mice.

Biomaterials 2017, 144, 30-41. 10.1016/j.biomaterials.2017.08.008

Gan Chen, Hongzhang Deng,Xiang Song, Mingzi Lu, Lian Zhao, Sha Xia, Guoxing You, Jingxiang Zhao, Yulong Zhang, Anjie Dong

Abstract

Sepsis-associated acute liver injury contributes to the pathogenesis of multiple organ dysfunction syndrome and is associated with increased mortality. Currently, no specific therapeutics for sepsis-associated liver injury are available. With excess levels of reactive oxygen species (ROS) being implicated as key players in sepsis-induced liver injury, we hypothesize that ROS-responsive nanoparticles (NPs) formed via the self-assembly of diblock copolymers of poly(ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) may function as an effective drug delivery system for alleviating sepsis-induced liver injury by preferentially releasing drug molecules at the disease site. However, there are no reports available on the biocompatibility and effect of PEG-b-PPS-NPs in vivo. Herein, this platform was tested for delivering the promising antioxidant therapeutic molecule melatonin (Mel), which currently has limited therapeutic efficacy because of its poor pharmacokinetic properties. The mPEG-b-PPS-NPs efficiently encapsulated Mel using the oil-in-water emulsion technique and provided sustained, on-demand release that was modulated in vitro by the hydrogen peroxide concentration. Animal studies using a mouse model of sepsis-induced acute liver injury revealed that Mel-loaded mPEG-b-PPS-NPs are biocompatible and much more efficacious than an equivalent amount of free drug in attenuating oxidative stress, the inflammatory response, and subsequent liver injury. Accordingly, this work indicates that mPEG-b-PPS-NPs show potential as an ROS-mediated on-demand drug delivery system for improving Mel bioavailability and treating oxidative stress-associated diseases such as sepsis-induced acute liver injury.

9.Tumor mmicroenvironment activated membrane fusogenic liposome with speedy antibody and doxorubicin delivery for synergistic treatment of metastatic tumors.

ACS Applied Materials & Interfaces 2017, 9, 9315-9326. 10.1021/acsami.6b14683

Hongzhang Deng, Kun Song, Xuefei Zhao, Yanan Li, Fei Wang, Jianhua Zhang, Anjie Dong, and Zhihai Qin

Abstract

Metastasis is the principal event leading to breast cancer death. Discovery of novel therapeutic approaches that are specific in targeting tumor metastasis factors while at the same time are an effective treatment of the tumor is urgently required. S100A4 protein is a key player in promoting metastasis and sequestrating the effect of tumor-suppressor protein p53. Here, a tumor microenvironment activated membrane fusogenic liposome was prepared to deliver rapidly anti-S100A4 antibody and doxorubicin into the cytoplasm directly in a fusion-dependent manner in order to bypass the cellular endocytosis to avoid the inefficient escape and degradation in the acidic endosome. After intracellular S100A4 blockage with anti-S100A4 antibody, the cytoskeleton of breast cancer 4T1 cells was rearranged and cell motility was suppressed. In the meantime, the antitumor effect of doxorubicin was enormously enhanced by reversing the effect of S100A4 on the sequestration of tumor-suppressor protein p53. Importantly, both local growth and metastasis of 4T1 cells were inhibited in a xenograft mouse model. Together, the speedy delivery of antibody and doxorubicin into cytoplasm based on a new membrane fusogenic liposome was an innovative approach for metastatic breast cancer treatment

       

8.Reactive oxygen species activated nanoparticles with tumor acidity internalization for precise anticancer therapy

Journal of Controlled Release 2017, 255, 142-153. 10.1016/j.jconrel.2017.04.002

Hongzhang Deng, Xuefei Zhao, Liandong Deng, Jianfeng Liu, Anjie Dong

Abstract

The fact that the sensitivities of different tumor cells and different individuals to the actions of drug delivery system varied greatly, restricted the anticarcinogen to a desired therapeutic concentration. How to determine the destiny of drug delivery system in space and time is the main challenge to realize the precise anticancer therapy. In this paper, we reported a preparation of degradable nanoparticles (designated Pros-PDC) loaded DOX and IR780 with three functional domains: the charge-conversional feature with long circulation time and enhanced internalization, light-triggered reactive oxygen species (ROS) generation and subsequently ROS responsive anticancer drug