bims-drudre 2021-09-26 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2021–09–26
twenty-two papers selected by
Ceren Kimna, Technical University of Munich

A siRNA-Assisted Assembly Strategy to Simultaneously Suppress "Self" and Upregulate "Eat-Me" Signals for Nanoenabled Chemo-Immunotherapy.
Apoptotic Tumor DNA Activated Nanomotor Chemotaxis.
Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity.
In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization.
Personalized Nanovaccine Coated with Calcinetin-Expressed Cancer Cell Membrane Antigen for Cancer Immunotherapy.
Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology.
Delivery of Cationic Platinum Prodrugs via Reduction Sensitive Polymer for Improved Chemotherapy.
Antibacterial Zeolite Imidazole Frameworks with Manganese Doping for Immunomodulation to Accelerate Infected Wound Healing.
Spatiotemporally dynamic therapy with shape-adaptive drug-gel for the improvement of tissue regeneration with ordered structure.
Both-In-One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem-Amplifying Reactive Oxygen Species-Immunity Responses.
Synthetic hydrogel nanoparticles for sepsis therapy.
NIR-activated self-sensitized polymeric micelles for enhanced cancer chemo-photothermal therapy.
Surface-fill hydrogel attenuates the oncogenic signature of complex anatomical surface cancer in a single application.
Heat-Confined Tumor-Docking Reversible Thermogel Potentiates Systemic Antitumor Immune Response During Near-Infrared Photothermal Ablation in Triple-Negative Breast Cancer.
Thymus Extracellular Matrix-Derived Scaffolds Support Graft-Resident Thymopoiesis and Long-Term In Vitro Culture of Adult Thymic Epithelial Cells.
Microenvironment-responsive DNA-conjugated albumin nanocarriers for targeted therapy.
Self-Assembling Peptide Dendron Nanoparticles with High Stability and a Multimodal Antimicrobial Mechanism of Action.
Acoustic Droplet Printing Tumor Organoids for Modeling Bladder Tumor Immune Microenvironment within a Week.
Construction of Messenger RNA (mRNA) Probes Delivered By Lipid Nanoparticles to Visualize Intracellular Protein Expression and Localization at Organelles.
Nature-Inspired Circular-Economy Recycling for Proteins: Proof of Concept.
Activatable Biomineralized Nanoplatform Remodels the Intracellular Environment of Multidrug-Resistant Tumors for Enhanced Ferroptosis/Apoptosis Therapy.
Controllable Synthesis of COFs-Based Multicomponent Nanocomposites from Core-Shell to Yolk-Shell and Hollow-Sphere Structure for Artificial Photosynthesis.

ACS Nano. 2021 Sep 20.

A siRNA-Assisted Assembly Strategy to Simultaneously Suppress "Self" and Upregulate "Eat-Me" Signals for Nanoenabled Chemo-Immunotherapy.

Yuxi Zhang, Zhenghai Zhang, Senlin Li, Liang Zhao, Dongdong Li, Ziyang Cao, Xiaoding Xu, Xianzhu Yang.

  Effectively activating macrophages that can engulf cancer cells is a promising immunotherapeutic strategy but remains a major challenge due to the expression of "self" signals (e.g., CD47 molecules) by tumor cells to prevent phagocytosis. Herein, we explored a siRNA-assisted assembly strategy for the simultaneous delivery of siRNA and mitoxantrone hydrochloride (MTO·2HCl) via PLGA-based nanoparticles. The siRNA suppressed a "self" signal by silencing the CD47 gene, while the MTO induced surface exposure of calreticulin (CRT) to provide an "eat-me" signal. The siRNA-assisted assembly strategy synergistically increased the phagocytosis of tumor cells by macrophages, promoted effective antigen presentation, and initiated T cell-mediated immune responses in two aggressive tumor animal models of melanoma and colon cancer, eventually achieving significantly improved antitumor activity. This study provides a straightforward codelivery strategy to simultaneously suppress "self" and upregulate "eat-me" signals to potentiate macrophage-mediated immunotherapy.

Keywords:  CD47-SIRPα signaling; CRT exposure; immunotherapy; macrophage phagocytosis; siRNA-assisted assembly strategy

DOI:  https://doi.org/10.1021/acsnano.1c04458
Nano Lett. 2021 Sep 24.

Apoptotic Tumor DNA Activated Nanomotor Chemotaxis.

Yicheng Ye, Fei Tong, Shuanghu Wang, Jiamiao Jiang, Junbin Gao, Lu Liu, Kun Liu, Fei Wang, Zhen Wang, Juanfeng Ou, Bin Chen, Daniela A Wilson, Yingfeng Tu, Fei Peng.

  Inspired by the tactic organisms in Nature that can self-direct their movement following environmental stimulus gradient, we proposed a DNase functionalized Janus nanoparticle (JNP) nanomotor system for the first time, which can be powered by ultralow nM to μM levels of DNA. The system exhibited interesting chemotactic behavior toward a DNA richer area, which is physiologically related with many diseases including tumors. In the presence of the subtle DNA gradient generated by apoptotic tumor cells, the cargo loaded nanomotors were able to sense the DNA signal released by the cells and demonstrate directional motion toward tumor cells. For our system, the subtle DNA gradient by a small amount (10 μL) of tumor cells is sufficient to induce the chemotaxis behavior of self-navigating and self-targeting ability of our nanomotor system, which promises to shed new light for tumor diagnosis and therapy.

Keywords:  DNase; Janus nanomotors; chemotaxis; self-navigating; tumor

DOI:  https://doi.org/10.1021/acs.nanolett.1c02441
Proc Natl Acad Sci U S A. 2021 09 28. pii: e2102595118. [Epub ahead of print]118(39):

Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity.

Cassie Caudill, Jillian L Perry, Kimon Iliadis, Addis T Tessema, Brian J Lee, Beverly S Mecham, Shaomin Tian, Joseph M DeSimone.

  Vaccination is an essential public health measure for infectious disease prevention. The exposure of the immune system to vaccine formulations with the appropriate kinetics is critical for inducing protective immunity. In this work, faceted microneedle arrays were designed and fabricated utilizing a three-dimensional (3D)-printing technique called continuous liquid interface production (CLIP). The faceted microneedle design resulted in increased surface area as compared with the smooth square pyramidal design, ultimately leading to enhanced surface coating of model vaccine components (ovalbumin and CpG). Utilizing fluorescent tags and live-animal imaging, we evaluated in vivo cargo retention and bioavailability in mice as a function of route of delivery. Compared with subcutaneous bolus injection of the soluble components, microneedle transdermal delivery not only resulted in enhanced cargo retention in the skin but also improved immune cell activation in the draining lymph nodes. Furthermore, the microneedle vaccine induced a potent humoral immune response, with higher total IgG (Immunoglobulin G) and a more balanced IgG1/IgG2a repertoire and achieved dose sparing. Furthermore, it elicited T cell responses as characterized by functional cytotoxic CD8+ T cells and CD4+ T cells secreting Th1 (T helper type 1)-cytokines. Taken together, CLIP 3D-printed microneedles coated with vaccine components provide a useful platform for a noninvasive, self-applicable vaccination.

Keywords:  3D printing; continuous liquid interface production; microneedles; transdermal delivery; vaccine

DOI:  https://doi.org/10.1073/pnas.2102595118
Angew Chem Int Ed Engl. 2021 Sep 22.

In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization.

Hao Wang, Ruo-Chen Guo, Xue-Hao Zhang, Peng-Sheng Fan, Ben-Li Song, Zhi-Xiang Li, Zhong-Yu Duan, Zeng-Ying Qiao.

  Therapeutic peptides have been widely concerned because of their good biocompatibility, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization and anticancer efficacy. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK] 2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP) on the cell membrane, KYp can be dephosphorylated and self-assembles in situ , which induces the aggregation of ALP and the protein-lipid phase separation on the cell membrane. ALP is involved in the assembly of peptides, forming the large aggregates and entering cells, which leads to the enhanced permeability of cell membrane. Consequently, the peptide drugs internalization is ~2-fold enhanced compared to non-responsive peptide nanoparticle, and IC 50 value of KYp is approximately ~5 times lower than that of free peptide. Finally, the tumor of mice treated with KYp is suppressed effectively, showing the negligible side effect in vivo . Therefore, the in vivo self-assembly induced phase separation on the cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.

Keywords:  Cancer; Drug Delivery; Phase Separation; peptide internalization; self-assembly

DOI:  https://doi.org/10.1002/anie.202111839
Nano Lett. 2021 Sep 21.

Personalized Nanovaccine Coated with Calcinetin-Expressed Cancer Cell Membrane Antigen for Cancer Immunotherapy.

Xiang Xiong, Jingya Zhao, Jingmei Pan, Chunping Liu, Xing Guo, Shaobing Zhou.

  A cancer vaccine has been widely applied in clinical tumor therapy as one of the main strategies of immunotherapy. However, the traditional cancer vaccine for a single antigen has a low benefit rate due to the individual differences in patients. Here, we report a R837-loaded poly(lactic-co-glycolic acid) nanovaccine coated with a calcinetin (CRT)-expressed cancer cell membrane antigen for immunotherapy. The cell membrane antigen that possessed a complete antigen array was obtained by inducing immunogenic cell death in vitro, avoiding the severe systemic toxicity of chemotherapy in vivo. The nanovaccine codelivers the adjuvant R837 and the Luc-4T1 membrane antigen, triggering a personalized immune response to the corresponding tumor. Moreover, the calcinetin exposed on the surface of the nanovaccine induces the active uptake of dendritic cells, consequently enhancing the antitumor effect. Meanwhile, the nanovaccine activates immune memory cells to provide long-term protection. Our work provides a new strategy for a clinical personalized antitumor vaccine.

Keywords:  Tumor cell membrane; immunogenic cell death; immunotherapy; nanoparticles; nanovaccine

DOI:  https://doi.org/10.1021/acs.nanolett.1c03004
Nat Commun. 2021 Sep 24. 12(1): 5623

Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology.

David Osuna de la Peña, Sara Maria David Trabulo, Estelle Collin, Ying Liu, Shreya Sharma, Marianthi Tatari, Diana Behrens, Mert Erkan, Rita T Lawlor, Aldo Scarpa, Christopher Heeschen, Alvaro Mata, Daniela Loessner.

Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.

DOI: https://doi.org/10.1038/s41467-021-25921-9
Small. 2021 Sep 23. e2101804

Delivery of Cationic Platinum Prodrugs via Reduction Sensitive Polymer for Improved Chemotherapy.

Hao Chen, Yushu Wang, Yulin Liu, Lin Tang, Qingchun Mu, Xiangye Yin, Liuchun Zheng, Youbai Chen, Chaoyong Liu.

  A cationic monofunctional platinum anticancer drug, phenanthriplatin (PhenPt(II)), exhibits promising anticancer effect on various cancer cell lines. Unlike the conventional platinum(II) drugs, PhenPt(II) is more likely to bind the N7 adenosine base of DNA in situ, and consequently resulting in a unique cellular response profile and unusual potency. However, since this drug is positively charged, it can easily bind to plasma protein that leads to rapid systematic clearance and deleterious toxicities, which greatly limits its in vivo application. Herein, a lipophilic phenanthriplatin (PhenPt(IV)) prodrug is synthesized. To further reduce its toxicity, a negatively charged polymer P1 with reduction responsiveness is assembled with PhenPt(IV) to form PhenPt(IV) NPs. In comparison to cisplatin, PhenPt(IV) NPs exhibit up to 30 times greater in vitro potency against various cancer cell lines. Additionally, in vivo, no obvious side effect is found on PhenPt(IV) NPs. Significant enhancement in tumor accumulation and improvement of drug efficacy in 4T1 tumor model are demonstrated. Taken together, this study provides a promising strategy for the clinical translation of phenanthriplatin.

Keywords:  Pt(IV) prodrugs; cationic drugs; phenanthriplatin; reduction sensitive polymers

DOI:  https://doi.org/10.1002/smll.202101804
Adv Healthc Mater. 2021 Sep 23. e2101515

Antibacterial Zeolite Imidazole Frameworks with Manganese Doping for Immunomodulation to Accelerate Infected Wound Healing.

Yao Wan, Jiao Fang, Yu Wang, Jiao Sun, Yue Sun, Xiaolin Sun, Manlin Qi, Wen Li, Chunyan Li, Yanmin Zhou, Lin Xu, Biao Dong, Lin Wang.

  Numerous nanomedicines currently emerge to reduce the dramatic threat in antibiotics resistance for antibacterial application against severe bacterial infections, while it is restricted by over-reacted immune response to pathogenic bacteria. Herein, enzymatic activity is introduced into the zeolitic imidazolate framework-8 (ZIF-8) to achieve sterilization by releasing Zn ions, as well as inflammation regulation through the variable valence of Mn ions that are uniformly doped into its framework. Within this simple metal organic framework (MOF) structure design, Mn-ZIF-8 possesses the co-existence of Mn2+ /Mn4+ to endow the nanocomposite with the anti-inflammatory capabilities, which can be adjusted through the redox environment. The enzymatic activity of Mn ions and superiority of pore structure of ZIF-8 are effectively combined to realize the substrate selection via reactant molecular size and high-efficiency internal catalytic performance. By such design, this nanocomposite would not only exhibit an excellent antibacterial performance against pathogenic bacteria, but also reshape the inflammatory immunity by regulating macrophage polarization to suppress over-reacted inflammation, leading to a favorably therapeutic efficiency on bacteria-infected wound healing in animal models. Taken together, this nanoplatform provides effective approach for accelerating infected wound healing via bacteria killing and inflammation modulation, and may be extended for the therapy of other severe bacteria-induced infections.

Keywords:  antibacterial; inflammation; macrophage polarization; nanomedicine; wound healing

DOI:  https://doi.org/10.1002/adhm.202101515
Bioact Mater. 2022 Feb;8 165-176

Spatiotemporally dynamic therapy with shape-adaptive drug-gel for the improvement of tissue regeneration with ordered structure.

Ya-Nan Fu, Yongsan Li, Bo Deng, Yingjie Yu, Fang Liu, Lei Wang, Guang Chen, Lei Tao, Yen Wei, Xing Wang.

  A spatiotemporally dynamic therapy (SDT) is proposed as a powerful therapeutic modality that provides spatially dynamic responses of drug-carriers for adapting to the wound microenvironment. Herein, dynamic chitosan-poly (ethylene glycol) (CP) Schiff-base linkages are employed to perform SDT by directly converting a liquid drug Kangfuxin (KFX) into a gel formation. The obtained KFX-CP drug-gel with shape-adaptive property is used to treat a representative oral mucositis (OM) model in a spatiotemporally dynamic manner. The KFX-CP drug-gel creates an instructive microenvironment to regulate signaling biomolecules and endogenous cells behavior, thereby promoting OM healing by the rule of dynamically adjusting shape to fit the irregular OM regions first, and then provides space for tissue regeneration, over KFX potion control and the general hydrogel group of CP hydrogel and KFX-F127. Most interestingly, the regenerated tissue has ordered structure like healthy tissue. Therefore, the SDT provides a new approach for the design of next generation of wound dressing and tissue engineering materials.

Keywords:  Drug-gel; Ordered structure; Shape-adaptive; Spatiotemporally dynamic therapy; Tissue regeneration

DOI:  https://doi.org/10.1016/j.bioactmat.2021.06.015
Adv Healthc Mater. 2021 Sep 20. e2100950

Both-In-One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem-Amplifying Reactive Oxygen Species-Immunity Responses.

Mengchi Sun, Hao Ye, Qinghua Shi, Jun Xie, Xiang Yu, Hao Ling, Song You, Zhonggui He, Bin Qin, Jin Sun.

  Bacterial therapy, which targets the tumor site and aims at exerting an antitumor immune response, has displayed a great potential against malignant tumors. However, failure of the phase I clinical trial of Salmonella strain VNP20009 alone demonstrates that bacterial treatment alone can unsatisfy the requirements of high efficiency and biosafety. Herein, a strategy of both-in-one hybrid bacteria is proposed, wherein the chemotherapeutic drug doxorubicin (DOX) is integrated onto the surface of glucose dehydrogenase (GDH)-overexpressed non-pathogenic Escherichia coli (E. coli) strain, to potentiate the antitumor efficacy. Nicotinamide adenine dinucleotide phosphate (NADPH), which is produced by GDH from E. coli, promotes the generation of toxic reactive oxygen species (ROS) within the tumor, and ROS is then catalyzed by the DOX-activated NADPH oxidases. Importantly, the hybrid bacteria enhance stimulated systemic antitumor immune responses, thereby leading to effective tumor eradication. When this strategy is applied in four different tumor models, the hybrid bacteria significantly inhibited tumor metastasis, postsurgical regrowth, and primary/distal tumor relapse. The both-in-one ROS-immunity-boosted hybrid bacteria strategy provides knowledge for the rational design of bacteria-based synergistic cancer therapy.

Keywords:  both-in-one hybrid bacteria; non-pathogenic Escherichia coli strain; reactive oxygen species-immunity-boosted; synergistic cancer therapy; toxic reactive oxygen species

DOI:  https://doi.org/10.1002/adhm.202100950
Nat Commun. 2021 09 21. 12(1): 5552

Synthetic hydrogel nanoparticles for sepsis therapy.

Hiroyuki Koide, Anna Okishima, Yu Hoshino, Yuri Kamon, Keiichi Yoshimatsu, Kazuhiro Saito, Ikumi Yamauchi, Saki Ariizumi, Yuqi Zhou, Ting-Hui Xiao, Keisuke Goda, Naoto Oku, Tomohiro Asai, Kenneth J Shea.

Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

DOI: https://doi.org/10.1038/s41467-021-25847-2
J Control Release. 2021 Sep 15. pii: S0168-3659(21)00496-X. [Epub ahead of print]

NIR-activated self-sensitized polymeric micelles for enhanced cancer chemo-photothermal therapy.

Lijun Yang, Xiaoxue Hou, Yumin Zhang, Dianyu Wang, Jinjian Liu, Fan Huang, Jianfeng Liu.

  NIR-activated therapies based on light-responsive drug delivery systems are emerging as a remote-controlled method for cancer precise therapy. In this work, fluorescent dye indocyanine green (ICG)-conjugated and bioactive compound gambogic acid (GA)-loaded polymeric micelles (GA@PEG-TK-ICG PMs) were smoothly fabricated via the self-assembly of the reactive oxygen species (ROS)-responsive thioketal (TK)-linked amphiphilic polymer poly(ethyleneglycol)-thioketal-(indocyanine green) (PEG-TK-ICG). The resultant micelles demonstrated increased resistance to photobleaching, enhanced photothermal conversion efficiency, NIR-controlled drug release behavior, preferable biocompatibility, and excellent tumor accumulation performance. Moreover, upon an 808 nm laser irradiation, the micellar photoactive chromophore ICG converted the absorbed optical energy to both hyperthermia for photothermal therapy (PTT) and ROS as the feedback trigger to the micelles for the tumor-specific release of GA, which could serve as not only a chemotherapeutic drug to directly kill tumor cells but also a heat shock protein 90 (HSP90) inhibitor to realize the photothermal sensitization. As a result, an extremely high tumor inhibition rate (97.9%) of mouse 4 T1 breast cancer models was achieved with negligible side effects after the chemo-photothermal synergistic therapy. This NIR-activated nanosystem with photothermal self-sensitization function may provide a feasible option for the effective treatment of aggressive breast cancers.

Keywords:  Chemo-photothermal therapy; Gambogic acid; Heat shock protein; NIR-activated nanosystem; Self-sensitization

DOI:  https://doi.org/10.1016/j.jconrel.2021.09.017
Nat Nanotechnol. 2021 Sep 23.

Surface-fill hydrogel attenuates the oncogenic signature of complex anatomical surface cancer in a single application.

Poulami Majumder, Anand Singh, Ziqiu Wang, Kingshuk Dutta, Roma Pahwa, Chen Liang, Caroline Andrews, Nimit L Patel, Junfeng Shi, Natalia de Val, Scott T R Walsh, Albert Byungyun Jeon, Baktiar Karim, Chuong D Hoang, Joel P Schneider.

Tumours growing in a sheet-like manner on the surface of organs and tissues with complex topologies represent a difficult-to-treat clinical scenario. Their complete surgical resection is difficult due to the complicated anatomy of the diseased tissue. Residual cancer often responds poorly to systemic therapy and locoregional treatment is hindered by the limited accessibility to microscopic tumour foci. Here we engineered a peptide-based surface-fill hydrogel (SFH) that can be syringe- or spray-delivered to surface cancers during surgery or used as a primary therapy. Once applied, SFH can shape change in response to alterations in tissue morphology that may occur during surgery. Implanted SFH releases nanoparticles composed of microRNA and intrinsically disordered peptides that enter cancer cells attenuating their oncogenic signature. With a single application, SFH shows efficacy in four preclinical models of mesothelioma, demonstrating the therapeutic impact of the local application of tumour-specific microRNA, which might change the treatment paradigm for mesothelioma and possibly other surface cancers.

DOI: https://doi.org/10.1038/s41565-021-00961-w
Adv Healthc Mater. 2021 Sep 20. e2100907

Heat-Confined Tumor-Docking Reversible Thermogel Potentiates Systemic Antitumor Immune Response During Near-Infrared Photothermal Ablation in Triple-Negative Breast Cancer.

Vishnu Revuri, Santhosh Kalash Rajendrakumar, Myong-Suk Park, Adityanarayan Mohapatra, Saji Uthaman, Jagannath Mondal, Woo Kyun Bae, In-Kyu Park, Yong-Kyu Lee.

  Triple-negative breast cancer (TNBC) features immunologically "cold" tumor microenvironments with limited cytotoxic T lymphocyte (CTL) infiltration. Although ablation therapies have demonstrated modulation of "cold" TNBC tumors to inflamed "hot" tumors, recruitment of myeloid derived suppressor cells (MDSCs) at the tumors post ablation therapies prevents the infiltration of CTLs and challenge the antitumor potentials of T-cell therapies. Here, a thermal ablation immunotherapy strategy is developed to prevent the immune suppressive effects of MDSCs during photothermal ablation and induce a durable systemic antitumor immunity to eradicate TNBC tumors. An injectable pluronic F127/hyaluronic acid (HA)-based hydrogel embedded with manganese dioxide (BM) nanoparticles and TLR7 agonist resiquimod (R848) (BAGEL-R848), is synthesized to induce in situ laser-assisted gelation of the hydrogel and achieve desired ablation temperatures at a low laser-exposure time. Upon 808-nm laser irradiation, a significant reduction in the tumor burden is observed in BAGEL-R848-injected 4T1 tumor-bearing mice. The ablation induced immunogenic cell death and sustained release of R848 from BAGEL-R848 promotes dendritic cell maturation and reduced MDSCs localization in tumors. In addition, inflammatory M1 macrophages and CD8+IFN+ CTL are enriched in distant tumors in bilateral 4T1 tumor model, preventing metastatic tumor growth and signifying the potential of BAGEL-R848 to treat TNBC.

Keywords:  Resiquimod; breast cancer; myeloid-derived suppressor cells; photothermal immunotherapy

DOI:  https://doi.org/10.1002/adhm.202100907
Adv Funct Mater. 2021 May 17. 31(20): 2010747

Thymus Extracellular Matrix-Derived Scaffolds Support Graft-Resident Thymopoiesis and Long-Term In Vitro Culture of Adult Thymic Epithelial Cells.

M Adelaide Asnaghi, Thomas Barthlott, Fabiana Gullotta, Valentina Strusi, Anna Amovilli, Katrin Hafen, Gitika Srivastava, Philipp Oertle, Roberto Toni, David Wendt, Georg A Holländer, Ivan Martin.

  The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of stroma cells provides surface-bound and soluble molecules that orchestrate the intrathymic maturation and selection of developing T cells. Forming an intricate 3D architecture, thymic epithelial cells (TEC) represent the most abundant and important constituent of the thymic stroma. Effective models for in and ex vivo use of adult TEC are still wanting, limiting the engineering of functional thymic organoids and the understanding of the development of a competent immune system. Here a 3D scaffold is developed based on decellularized thymic tissue capable of supporting in vitro and in vivo thymopoiesis by both fetal and adult TEC. For the first time, direct evidences of feasibility for sustained graft-resident T-cell development using adult TEC as input are provided. Moreover, the scaffold supports prolonged in vitro culture of adult TEC, with a retained expression of the master regulator Foxn1. The success of engineering a thymic scaffold that sustains adult TEC function provides unprecedented opportunities to investigate thymus development and physiology and to design and implement novel strategies for thymus replacement therapies.

Keywords:  3D scaffolds; decellularization; thymic epithelial cells; thymus engineering

DOI:  https://doi.org/10.1002/adfm.202010747
J Mater Chem B. 2021 Sep 20.

Microenvironment-responsive DNA-conjugated albumin nanocarriers for targeted therapy.

Jiayu Yu, Jianing Zhang, Jing Jin, Wei Jiang.

Drug delivery with accurate targeting and efficient treatment has become an essential strategy for cancer therapy. Two nanocarriers based on bovine serum albumin (BSA) and DNA were synthesized via click chemistry and DNA hybridization reactions (DNA-BSA1 and DNA-BSA2). One of the hybridized oligonucleotides, Linker1, in DNA-BSA1 included a pH-sensitive i-motif sequence and a cancer cell-targeted guanine-quadruplex-structured AS1411 aptamer sequence, and the other, Linker2, in DNA-BSA2 had only the same pH-sensitive i-motif sequence. Doxorubicin (DOX) molecules could be quickly and preferentially intercalated into double-stranded DNA via non-covalent interactions, and the encapsulation efficiency of DNA-BSA1 and DNA-BSA2 was almost 100% and 87.5%, respectively. As a mimic of the cancer cell microenvironment, a pH-trigger and a deoxyribonuclease I (DNase I)-trigger release mechanism was individually proposed to explain the dynamic release of the DNA-BSA@DOX under acidic conditions and the presence of DNase I in vitro. Intracellular uptake and cytotoxicity experiments confirmed that the nanocarrier DNA-BSA1@DOX had accurate targeting and efficient treatment towards cancer cells due to the high affinity and specificity of AS1411 to nucleolin, which is overexpressed in cancer cells. Furthermore, in vivo studies showed that the nanocarrier system could efficiently inhibit tumor growth. Therefore, the entire bio-based nanocarrier DNA-BSA is a promising candidate for the loading and release of anti-cancer drugs for accurate delivery and efficient treatment.

DOI: https://doi.org/10.1039/d1tb01022k
ACS Nano. 2021 Sep 22.

Self-Assembling Peptide Dendron Nanoparticles with High Stability and a Multimodal Antimicrobial Mechanism of Action.

Zhenheng Lai, Qiao Jian, Guoyu Li, Changxuan Shao, Yongjie Zhu, Xiaojie Yuan, Hongyu Chen, Anshan Shan.

  Self-assembling nanometer-scale structured peptide polymers and peptide dendrimers have shown promise in biomedical applications due to their versatile properties and easy availability. Herein, self-assembling peptide dendron nanoparticles (SPDNs) with potent antimicrobial activity against a range of bacteria were developed based on the nanoscale self-assembly of an arginine-proline repeat branched peptide dendron bearing a hexadecanoic acid chain. The SPDNs are biocompatible, and our most active peptide dendron nanoparticle, C16-3RP, was found to have negligible toxicity after both in vitro and in vivo studies. Furthermore, the C16-3RP nanoparticles showed excellent stability under physiological concentrations of salt ions and against serum and protease degradation, resulting in highly effective treatment in a mouse acute peritonitis model. Comprehensive analyses using a series of biofluorescence, microscopy, and transcriptome sequencing techniques revealed that C16-3RP nanoparticles kill Gram-negative bacteria by increasing bacterial membrane permeability, inducing cytoplasmic membrane depolarization and drastic membrane disruption, inhibiting ribosome biogenesis, and influencing energy generation and other processes. Collectively, C16-3RP nanoparticles show promising biocompatibility and in vivo therapeutic efficacy without apparent resistance development. These advancements may facilitate the development of peptide-based antibiotics in clinical settings.

Keywords:  in vivo efficacy; mechanism of action; peptide dendron; self-assembling nanoparticles; stability

DOI:  https://doi.org/10.1021/acsnano.1c03301
Adv Healthc Mater. 2021 Sep 23. e2101312

Acoustic Droplet Printing Tumor Organoids for Modeling Bladder Tumor Immune Microenvironment within a Week.

Zhiyi Gong, Lanxiang Huang, Xuan Tang, Keke Chen, Zhuhao Wu, Lingling Zhang, Yue Sun, Yu Xia, Hui Chen, Yongchang Wei, Fubing Wang, Shishang Guo.

  Current organoid models are limited by the incapability of rapidly fabricating organoids that can mimic the immune microenvironment for a short term. Here, an acoustic droplet-based platform is presented to facilitate the rapid formation of tumor organoids, which retains the original tumor immune microenvironment and establishes a personalized bladder cancer tumor immunotherapy model. In combination with a hydrophobic substrate, the acoustic droplet printer can yield a large number of homogeneous and highly viable bladder tumor organoids in vitro within a week. The generated organoids consist of all components of bladder tumor, including diverse immune elements and tumor cells. By coculturing tumor organoids with autologous immune cells for 2 days, tumor reactive T cells are induced in vitro. Furthermore, it is also demonstrated that these tumor-reactive T cells can also enhance the killing efficiency of matched organoids. Because of the easy operation, repeatability, and stability, the proposed acoustic droplet platform will provide a reliable approach for personalized tumor immunotherapy.

Keywords:  T cells; acoustic droplets; cocultures; tumor microenvironments; tumor organoids

DOI:  https://doi.org/10.1002/adhm.202101312
Adv Mater. 2021 Sep 20. e2103131

Construction of Messenger RNA (mRNA) Probes Delivered By Lipid Nanoparticles to Visualize Intracellular Protein Expression and Localization at Organelles.

Weiyu Zhao, Chunxi Zeng, Jingyue Yan, Shi Du, Xucheng Hou, Chengxiang Zhang, Wenqing Li, Binbin Deng, David W McComb, Yonger Xue, Diana D Kang, Yizhou Dong.

  Organelles are specialized compartments, where various proteins reside and play crucial roles to maintain essential cellular structures and functions in mammalian cells. A comprehensive understanding of protein expressions and subsequent localizations at each organelle is of great benefit to the development of organelle-based therapies. Herein, a set of single or dual organelle labeling messenger RNAs (SOLAR or DOLAR) is designed as novel imaging probes, which encode fluorescent proteins with various organelle localization signals. These mRNA probes enable to visualize the protein localizations at different organelles and investigate their trafficking from ribosomal machinery to specific organelles. According to the in vitro results, SOLAR probes show organelle targeting capabilities consistent with the design. Moreover, DOLAR probes with different linkers display distinct targeting properties depending on different organelle localization signals. Additionally, these mRNA probes also exhibit organelle labeling ability in vivo when delivered by lipid nanoparticles (LNPs). Therefore, these mRNA-based probes provide a unique tool to study cell organelles and may facilitate the design of organelle-based therapies.

Keywords:  lipid nanoparticles; mRNA probes; organelle targeting; protein translocation

DOI:  https://doi.org/10.1002/adma.202103131
Adv Mater. 2021 Sep 23. e2104581

Nature-Inspired Circular-Economy Recycling for Proteins: Proof of Concept.

Simone Giaveri, Adeline Marie Schmitt, Laura Roset Julià, Vincenzo Scamarcio, Anna Murello, Shiyu Cheng, Laure Menin, Daniel Ortiz, Luc Patiny, Sreenath Bolisetty, Raffaele Mezzenga, Sebastian Josef Maerkl, Francesco Stellacci.

  The billion tons of synthetic-polymer-based materials (i.e. plastics) produced yearly are a great challenge for humanity. Nature produces even more natural polymers, yet they are sustainable. Proteins are sequence-defined natural polymers that are constantly recycled when living systems feed. Digestion is the protein depolymerization into amino acids (the monomers) followed by their re-assembly into new proteins of arbitrarily different sequence and function. This breaks a common recycling paradigm where a material is recycled into itself. Organisms feed off of random protein mixtures that are "recycled" into new proteins whose identity depends on the cell's specific needs. In this study, mixtures of several peptides and/or proteins are depolymerized into their amino acid constituents, and these amino acids are used to synthesize new fluorescent, and bioactive proteins extracellularly by using an amino-acid-free, cell-free transcription-translation (TX-TL) system. Specifically, three peptides (magainin II, glucagon, and somatostatin 28) are digested using thermolysin first and then using leucine aminopeptidase. The amino acids so produced are added to a commercial TX-TL system to produce fluorescent proteins. Furthermore, proteins with high relevance in materials engineering (β-lactoglobulin films, used for water filtration, or silk fibroin solutions) are successfully recycled into biotechnologically relevant proteins (fluorescent proteins, catechol 2,3-dioxygenase).

Keywords:  protein-based materials; recycling; sequence-defined polymers; sustainability

DOI:  https://doi.org/10.1002/adma.202104581
Small. 2021 Sep 23. e2102269

Activatable Biomineralized Nanoplatform Remodels the Intracellular Environment of Multidrug-Resistant Tumors for Enhanced Ferroptosis/Apoptosis Therapy.

Xuan Wang, Yuanyuan Zhao, Yan Hu, Yang Fei, Youbo Zhao, Chencheng Xue, Kaiyong Cai, Menghuan Li, Zhong Luo.

  Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe2+ (DOX-Fe2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H2 O2 production, but also increase the overall catalytic efficiency of Fe2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.

Keywords:  biomineralized nanoplatforms; ferroptosis therapies; iron-drug nanocomplexes; multidrug-resistant tumors; tumor intracellular remodeling

DOI:  https://doi.org/10.1002/smll.202102269
Adv Mater. 2021 Sep 24. e2105002

Controllable Synthesis of COFs-Based Multicomponent Nanocomposites from Core-Shell to Yolk-Shell and Hollow-Sphere Structure for Artificial Photosynthesis.

Mi Zhang, Jia-Nan Chang, Yifa Chen, Meng Lu, Tao-Yuan Yu, Cheng Jiang, Shun-Li Li, Yue-Peng Cai, Ya-Qian Lan.

  The precise tuning and multi-dimensional processing of covalent organic frameworks (COFs)-based materials into multicomponent superstructures with appropriate diversity are essential to maximize their advantages in catalytic reactions. However, up to now, it remains an ongoing challenge for the precise design of COFs-based multicomponent nanocomposites with diverse architectures. Herein, a metal organic framework (MOF)-sacrificed in situ acid-etching (MSISAE) strategy that enables continuous synthesis of core-shell, yolk-shell, and hollow-sphere COFs-based nanocomposites through tuning of core decomposition (NH2 -MIL-125 into TiO2 ) rate is developed. More importantly, due to the multiple active sites, fast transfer of carriers, increased light utilization ability, et al, one of the obtained samples, NH2 -MIL-125/TiO2 @COF-366-Ni-OH-HAc (yolk-shell) with special three components, exhibits high photocatalytic CO2 -to-CO conversion efficiency in the gas-solid mode. The MSISAE strategy developed in this work achieves the precise morphology design and control of multicomponent hybrid composites based on COFs, which may pave a new way in devealoping porous crystalline materials with powerful superstructures for multifunctional catalytic reactions.

Keywords:  artificial photosynthesis; covalent organic frameworks; diverse architectures; multicomponent nanocomposites

DOI:  https://doi.org/10.1002/adma.202105002