bims-drudre 2022-08-28 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–08–28
sixteen papers selected by
Ceren Kimna, Technical University of Munich

InSitu Programming of Nanovaccines for Lymph Node-Targeted Delivery and Cancer Immunotherapy.
Supramolecular erythrocytes-hitchhiking drug delivery system for specific therapy of acute pneumonia.
Sprayable hydrogel for instant sealing of vascular anastomosis.
Molecularly Engineered Protein Glues with Superior Adhesion Performance.
Unbreakable Hydrogels with Self-Recoverable 10200% Stretchability.
Biomimetic Neutrophil Nanotoxoids Elicit Potent Immunity against Acinetobacter baumannii in Multiple Models of Infection.
Inducible expression of large gRNA arrays for multiplexed CRISPRai applications.
Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.
The "Bloodless" Blood Test: Intradermal Prick Nanoelectronics for the Blood Extraction-Free Multiplex Detection of Protein Biomarkers.
Acetic Acid Enables Precise Tailoring of the Mechanical Behavior of Protein-Based Hydrogels.
Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy.
Injectable click-crosslinked hydrogel containing resveratrol to improve the therapeutic effect in triple negative breast cancer.
Bioinspired zwitterionic microgel-based coating: controllable microstructure, high stability, and anticoagulant properties.
Judicious Design and Rapid Manufacturing of Flexible, Mechanically Resistant Liquid-like Coating with Strong Bonding and Antifouling Abilities.
Albumin-Coated Framework Nucleic Acids as Bionic Delivery System for Triple-Negative Breast Cancer Therapy.
Programmed prodrug breaking the feedback regulation of P-selectin in plaque inflammation for atherosclerotic therapy.

ACS Nano. 2022 Aug 26.

InSitu Programming of Nanovaccines for Lymph Node-Targeted Delivery and Cancer Immunotherapy.

Liangjie Jin, Dongmei Yang, Yonghong Song, Dongdong Li, Weijia Xu, Yueqiang Zhu, Cong-Fei Xu, Yang Lu, Xianzhu Yang.

  In situ cancer vaccines consisting of antigens and adjuvants are a promising cancer treatment modality; however, the convenient manufacture of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remains a major challenge. Herein, we outline a facile approach to simultaneously achieve the in situ programming of vaccines via two synergetic nanomedicines, Tu-NPFN and Ln-NPR848. Tu-NPFN (∼100 nm) generated a large number of antigens under an alternating magnetic field, and Ln-NPR848 (∼35 nm) encapsulating adjuvant R848 captured a portion of generated antigens for the manufacture of nanovaccines in situ and LN-targeted delivery, which significantly promoted the uptake and maturation of dendritic cells to initiate potent anticancer immune responses. Notably, combined with an anti-CTLA4 antibody (aCTLA-4), this therapy completely eradicated distant tumors in some mice and exerted a long-term immune memory effect on tumor metastasis. This study provides a generalizable strategy for in situ cancer vaccination.

Keywords:  cancer immunotherapy; immune response; in situ cancer vaccines; lymph nodes-targeted delivery; nanovaccines

DOI:  https://doi.org/10.1021/acsnano.2c06560
J Control Release. 2022 Aug 19. pii: S0168-3659(22)00534-X. [Epub ahead of print]

Supramolecular erythrocytes-hitchhiking drug delivery system for specific therapy of acute pneumonia.

Junyan Li, Yuanfu Ding, Qian Cheng, Cheng Gao, Jianwen Wei, Ziyi Wang, Qiaoxian Huang, Ruibing Wang.

  Acute pneumonia is an inflammatory syndrome often associated with severe multi-organ dysfunction and high mortality. The therapeutic efficacy of current anti-inflammatory medicines is greatly limited due to the short systemic circulation and poor specificity in the lungs. New drug delivery systems (DDS) are urgently needed to efficiently transport anti-inflammatory drugs to the lungs. Here, we report an inflammation-responsive supramolecular erythrocytes-hitchhiking DDS to extend systemic circulation of the nanomedicine via hitchhiking red blood cells (RBCs) and specifically "drop off" the payloads in the inflammatory lungs. β-cyclodextrin (β-CD) modified RBCs and ferrocene (Fc) modified liposomes (NP) were prepared and co-incubated to attach NP to RBCs via β-CD/Fc host-guest interactions. RBCs extended the systemic circulation of the attached NP, meanwhile, the NP may get detached from RBCs due to the high ROS level in the inflammatory lungs. In acute pneumonia mice, this strategy delivered curcumin specifically to the lungs and effectively alleviated the inflammatory syndrome.

Keywords:  Acute pneumonia; Cyclodextrin; Host-guest interactions; Inflammation-responsive; RBC-hitchhiking

DOI:  https://doi.org/10.1016/j.jconrel.2022.08.029
Adv Mater. 2022 Aug 27. e2203087

Sprayable hydrogel for instant sealing of vascular anastomosis.

Gonzalo Muñoz Taboada, Pere Dosta, Elazer R Edelman, Natalie Artzi.

  Bleeding-related complications following vascular surgeries occur in up to half of the patients-500,000 cases annually in the US alone. This results in additional procedures, increased mortality rate, and prolonged hospitalization, posing a burden on the healthcare system. Commercially-available materials rely, in large, on forming covalent bonds between the tissue and the biomaterial to achieve adhesion. Here we show that a biomaterial based on oxidized alginate and oxidized dextran together with PAMAM dendrimer amine provides simultaneous electrostatic- and covalent-interactions between the biomaterial and the tissue, maximizing adhesion. We found that our material withstands supraphysiological pressures (∼300 mmHg) and prevents bleeding in a rabbit aortic puncture model and in a pig carotid bilateral polytetrafluoroethylene (ePTFE) graft model-achieving superior performance to commercially-available materials such as Tisseel and BioGlue. Material biocompatibility was validated in comprehensive in vitro and in vivo studies in accordance with the FDA guidelines, including in-vitro Neutral Red Uptake (NRU) test, subcutaneous implantation in rabbits, ames genotoxicity and guinea-pig maximization-test. This material has the potential to provide with adequate seal and reduced complications following complex vascular surgeries, including hard-to-seal tissue:graft interfaces. This article is protected by copyright. All rights reserved.

Keywords:  Adhesive hydrogel; Surgical sealant; Translational research

DOI:  https://doi.org/10.1002/adma.202203087
Adv Mater. 2022 Aug 25. e2204590

Molecularly Engineered Protein Glues with Superior Adhesion Performance.

Zili Wang, Xinquan Gu, Bo Li, Jingjing Li, Fan Wang, Jing Sun, Hongjie Zhang, Kai Liu, Weisheng Guo.

  Naturally inspired proteins have been investigated for the development of bioglues that combine adhesion performance and biocompatibility for biomedical applications. However, engineering such adhesives by rational design of the proteins at the molecular level is rarely reported. Herein, we show that a new generation of protein-based glues is generated by supramolecular assembly through de novo designed structural proteins in which the arginine triggers robust liquid-liquid phase separation. The encoded arginine moieties significantly strengthened multiple molecular interactions in the complex, leading to ultra-strong adhesion on various surfaces, outperforming many chemically reacted and biomimetic glues. Such adhesive materials enabled quick visceral hemostasis in 10 seconds and outstanding tissue regeneration due to their robust adhesion, good biocompatibility, and superior anti-bacterial capacity. Remarkably, their minimum inhibitory concentrations are orders of magnitude lower than clinical antibiotics. These advances offer insights into molecular engineering of de novo designed protein glues and outline a general strategy to fabricate mechanically strong protein-based materials for surgical applications. This article is protected by copyright. All rights reserved.

Keywords:  adhesion performance; adhesives; molecular engineering; structural proteins; wound healing

DOI:  https://doi.org/10.1002/adma.202204590
Adv Mater. 2022 Aug 24. e2206904

Unbreakable Hydrogels with Self-Recoverable 10200% Stretchability.

Shuai Tan, Caihong Wang, Baibin Yang, Jie Luo, Yong Wu.

  Design of tough hydrogels maintaining structural integrity under multivariable mechanical loads remains huge challenging because the anticipated characteristics such as stretchability, strength, toughness, and fracture resistance can hardly be compatible. Herein, we propose a simple but robust hydrogel network formed by copolymerization of divinyl benzene with acrylamide in micellar solutions to achieve both ultra-high fracture resistance and self-recoverable stretchability. The network provides dynamic association of hydrophobic domains and homogenous crosslinking of hydrophilic chains, which showed step-by-step deformation process for effective energy dissipation. The dynamic associations allow recoverable small deformations of hydrogels, then the homogenous crosslinking ensures reversible unfolding and alignment of polymer chains to self-strengthen for ultra-large deformations without crack propagations. The resultant hydrogels exhibit comprehensive unbreakable feature with self-recoverable ultra-high stretchability (100% recovery from 10200% strain), superior fracture resistance (fracture work > 18.8 MJ m-3 , toughness > 26 kJ m-2 ), and anti-crack propagation and fatigue (fatigue threshold: ∼ 2.5 kJ m-2 ). Even the pre-notched hydrogels can intriguingly undergo tens cyclic loads at 10200% strain and thousands cyclic loads at 200% strain without noticeable changes in mechanical performance. The robust network prepared from homogenous hydrophobic crosslinking provides a facile approach and a new mechanism to explore tough hydrogels with superior anti-fracture and extreme self-recoverable deformability for diverse applications . This article is protected by copyright. All rights reserved.

Keywords:  anti-fracture; homogenous hydrophobic crosslinking; hydrogels; self-recoverability; ultra-high deformations

DOI:  https://doi.org/10.1002/adma.202206904
Nano Lett. 2022 Aug 23.

Biomimetic Neutrophil Nanotoxoids Elicit Potent Immunity against Acinetobacter baumannii in Multiple Models of Infection.

Jiarong Zhou, Christian J Ventura, Yiyan Yu, Weiwei Gao, Ronnie H Fang, Liangfang Zhang.

  Acinetobacter baumannii is a leading cause of antibiotic-resistant nosocomial infections with high mortality rates, yet there is currently no clinically approved vaccine formulation. During the onset of A. baumannii infection, neutrophils are the primary responders and play a major role in resisting the pathogen. Here, we design a biomimetic nanotoxoid for antivirulence vaccination by using neutrophil membrane-coated nanoparticles to safely capture secreted A. baumannii factors. Vaccination with the nanotoxoid formulation rapidly mobilizes innate immune cells and promotes pathogen-specific adaptive immunity. In murine models of pneumonia, septicemia, and superficial wound infection, immunization with the nanovaccine offers significant protection, improving survival and reducing signs of acute inflammation. Lower bacterial burdens are observed in vaccinated animals regardless of the infection route. Altogether, neutrophil nanotoxoids represent an effective platform for eliciting multivalent immunity to protect against multidrug-resistant A. baumannii in a wide range of disease conditions.

Keywords:  Acinetobacter baumannii; nanovaccine; pneumonia; sepsis; wound infection

DOI:  https://doi.org/10.1021/acs.nanolett.2c01948
Nat Commun. 2022 Aug 25. 13(1): 4984

Inducible expression of large gRNA arrays for multiplexed CRISPRai applications.

William M Shaw, Lucie Studená, Kyler Roy, Piotr Hapeta, Nicholas S McCarty, Alicia E Graham, Tom Ellis, Rodrigo Ledesma-Amaro.

CRISPR gene activation and inhibition (CRISPRai) has become a powerful synthetic tool for influencing the expression of native genes for foundational studies, cellular reprograming, and metabolic engineering. Here we develop a method for near leak-free, inducible expression of a polycistronic array containing up to 24 gRNAs from two orthogonal CRISPR/Cas systems to increase CRISPRai multiplexing capacity and target gene flexibility. To achieve strong inducibility, we create a technology to silence gRNA expression within the array in the absence of the inducer, since we found that long gRNA arrays for CRISPRai can express themselves even without promoter. Using this method, we create a highly tuned and easy-to-use CRISPRai toolkit in the industrially relevant yeast, Saccharomyces cerevisiae, establishing the first system to combine simultaneous activation and repression, large multiplexing capacity, and inducibility. We demonstrate this toolkit by targeting 11 genes in central metabolism in a single transformation, achieving a 45-fold increase in succinic acid, which could be precisely controlled in an inducible manner. Our method offers a highly effective way to regulate genes and rewire metabolism in yeast, with principles of gRNA array construction and inducibility that should extend to other chassis organisms.

DOI: https://doi.org/10.1038/s41467-022-32603-7
Nat Commun. 2022 Aug 22. 13(1): 4918

Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.

Ying Xue Xie, Nima N Naseri, Jasmine Fels, Parinati Kharel, Yoonmi Na, Diane Lane, Jacqueline Burré, Manu Sharma.

Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson's disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca2+. These results propose lysosomal exocytosis as a central mechanism for the release of aggregated and degradation-resistant proteins from neurons.

DOI: https://doi.org/10.1038/s41467-022-32625-1
ACS Nano. 2022 Aug 25.

The "Bloodless" Blood Test: Intradermal Prick Nanoelectronics for the Blood Extraction-Free Multiplex Detection of Protein Biomarkers.

Nimrod Harpak, Ella Borberg, Adva Raz, Fernando Patolsky.

  Protein biomarkers' detection is of utmost importance for preventive medicine and early detection of illnesses. Today, their detection relies entirely on clinical tests consisting of painful, invasive extraction of large volumes of venous blood; time-consuming postextraction sample manipulation procedures; and mostly label-based complex detection approaches. Here, we report on a point-of-care (POC) diagnosis paradigm based on the application of intradermal finger prick-based electronic nanosensors arrays for protein biomarkers' direct detection and quantification down to the sub-pM range, without the need for blood extraction and sample manipulation steps. The nanobioelectronic array performs biomarker sensing by a rapid intradermal prick-based sampling of proteins biomarkers directly from the capillary blood pool accumulating at the site of the microneedle puncture, requiring only 2 min and less than one microliter of a blood sample for a complete analysis. A 1 mm long microneedle element was optimal in allowing for pain-free dermal sampling with a 100% success rate of reaching and rupturing dermis capillaries. Current common micromachining processes and top-down fabrication techniques allow the nanobioelectronic sensor arrays to provide accurate and reliable clinical diagnostic results using multiple sensing elements in each microneedle and all-in-one direct and label-free multiplex biomarkers detection. Preliminary successful clinical studies performed on human volunteers demonstrated the ability of our intradermal, in-skin, blood extraction-free detection platform to accurately detect protein biomarkers as a plausible POC detection for future replacement of today's invasive clinical blood tests. This approach can be readily extended in the future to detect other clinically relevant circulating biomarkers, such as miRNAs, free-DNAs, exosomes, and small metabolites.

Keywords:  Biomarkers; Biomolecules; Detection; Nanobioelectronics; Nanosensors

DOI:  https://doi.org/10.1021/acsnano.2c01793
Nano Lett. 2022 Aug 26.

Acetic Acid Enables Precise Tailoring of the Mechanical Behavior of Protein-Based Hydrogels.

Marina Slawinski, Maria Kaeek, Yair Rajmiel, Luai R Khoury.

  Engineering viscoelastic and biocompatible materials with tailored mechanical and microstructure properties capable of mimicking the biological stiffness (<17 kPa) or serving as bioimplants will bring protein-based hydrogels to the forefront in the biomaterials field. Here, we introduce a method that uses different concentrations of acetic acid (AA) to control the covalent tyrosine-tyrosine cross-linking interactions at the nanoscale level during protein-based hydrogel synthesis and manipulates their mechanical and microstructure properties without affecting protein concentration and (un)folding nanomechanics. We demonstrated this approach by adding AA as a precursor to the preparation buffer of a photoactivated protein-based hydrogel mixture. This strategy allowed us to synthesize hydrogels made from bovine serum albumin (BSA) and eight repeats protein L structure, with a fine-tailored wide range of stiffness (2-35 kPa). Together with protein engineering technologies, this method will open new routes in developing and investigating tunable protein-based hydrogels and extend their application toward new horizons.

Keywords:  Biomaterials; Dynamic hydrogels; Protein folding transitions; Protein-based hydrogels; Responsive biomaterials

DOI:  https://doi.org/10.1021/acs.nanolett.2c01558
ACS Nano. 2022 Aug 26.

Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy.

Xiang Li, Qinghao Zhou, Abd Al-Wali Mohammed M Japir, Debabrata Dutta, Nannan Lu, Zhishen Ge.

  Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H2O2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

Keywords:  ROS-responsive; chemodynamic therapy; immune checkpoint blockade; immunotherapy; nanocomplex

DOI:  https://doi.org/10.1021/acsnano.2c06026
Mater Today Bio. 2022 Dec;16 100386

Injectable click-crosslinked hydrogel containing resveratrol to improve the therapeutic effect in triple negative breast cancer.

Gi Ru Shin, Hee Eun Kim, Hyeon Jin Ju, Jae Ho Kim, Sangdun Choi, Hak Soo Choi, Moon Suk Kim.

  Triple-negative breast cancer (TNBC) patients are considered intractable, as this disease has few effective treatments and a very poor prognosis even in its early stages. Here, intratumoral therapy with resveratrol (Res), which has anticancer and metastasis inhibitory effects, was proposed for the effective treatment of TNBC. An injectable Res-loaded click-crosslinked hyaluronic acid (Res-Cx-HA) hydrogel was designed and intratumorally injected to generate a Res-Cx-HA depot inside the tumor. The Res-Cx-HA formulation exhibited good injectability into the tumor tissue, quick depot formation inside the tumor, and the depot remained inside the injected tumor for extended periods. In vivo formed Res-Cx-HA depots sustained Res inside the tumor for extended periods. More importantly, the bioavailability and therapeutic efficacy of Res remained almost exclusively within the tumor and not in other organs. Intratumoral injection of Res-Cx-HA in animal models resulted in significant negative tumor growth rates (i.e., the tumor volume decreased over time) coupled with large apoptotic cells and limited angiogenesis in tumors. Therefore, Res-Cx-HA intratumoral injection is a promising way to treat TNBC patients with high efficacy and minimal adverse effects.

Keywords:  Click-crosslinking; Injectable hydrogel; Intratumoral injection; Resveratrol; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.mtbio.2022.100386
Acta Biomater. 2022 Aug 19. pii: S1742-7061(22)00498-6. [Epub ahead of print]

Bioinspired zwitterionic microgel-based coating: controllable microstructure, high stability, and anticoagulant properties.

Mengmeng Yao, Xia Sun, Zhicheng Guo, Zhongming Zhao, Zhuojun Yan, Fanglian Yao, Hong Zhang, Junjie Li.

  Zwitterionic polymers have shown promising results in non-fouling and preventing thrombosis. However, the lack of controlled surface coverage hinders their application for biomedical devices. Inspired by the natural biological surfaces, a facile zwitterionic microgel-based coating strategy is developed by the co-deposition of poly (sulfobetaine methacrylate-co-2-aminoethyl methacrylate) microgel (SAM), polydopamine (PDA), and sulfobetaine-modified polyethyleneimine (PES). The SAMs were used to construct controllable morphology by using the PDA combined with PES (PDAS) as the intermediate layer, which can be easily modulated via adjusting the crosslinking degree and contents of SAMs. The obtained SAM/PDAS coatings exhibit high anti-protein adhesive properties and can effectively inhibit the adhesion of cells, bacteria, and platelet through the synergy of high deposition density and controllable morphology. In addition, the stability of SAM/PDAS coating is improved owing to the anchoring effects of PDAS to substrate and SAMs. Importantly, the ex vivo blood circulation test in rabbits suggests that the SAM/PDAS coating can effectively decrease thrombosis without anticoagulants. This study provides a versatile coating method to address the integration of zwitterionic microgel-based coatings with high deposition density and controllable morphology onto various substrates for wide biomedical device applications. STATEMENT OF SIGNIFICANCE: Thrombosis is a major cause of medical device implantation failure, which results in significant morbidity and mortality. In this study, inspired by natural biological surfaces (fish skin and vascular endothelial layer) and the anchoring ability of mussels, we report a convenient and efficient method to firmly anchor zwitterionic microgels using an oxidative co-deposition strategy. The prepared coating has excellent antifouling and antithrombotic properties through the synergistic effect of physical morphology and chemical composition. This biomimetic surface engineering strategy is expected to provide new insights into the clinical problems of blood-contacting devices related to thrombosis.

Keywords:  Antithrombotic; Bionic microstructure; Microgels; Non-fouling; Zwitterions

DOI:  https://doi.org/10.1016/j.actbio.2022.08.022
Adv Mater. 2022 Aug 26. e2204581

Judicious Design and Rapid Manufacturing of Flexible, Mechanically Resistant Liquid-like Coating with Strong Bonding and Antifouling Abilities.

Weiwei Zheng, Jianying Huang, Xuerui Zang, Xuanfei Xu, Weilong Cai, Zhiqun Lin, Yuekun Lai.

  Fluorine-free liquid-repellent coatings have been highly demanded for a variety of applications. However, rapid formation of coatings possessing outstanding oil repellency and strong bonding ability as well as good mechanical strength (e.g., bendability, impact resistance, and scratch resistance) remains a grand challenge. Herein, we report a robust strategy to rapidly create fluorine-free oil-repellent coatings in only 30 s via rational design of a semi-interpenetrating polymer network structure. The resulting coating manifests strong bonding capability both in air and underwater. More importantly, it not only provides unprecedented oil repellency, even to high-viscosity crude oil, but also achieves both excellent bendability and hardness. Our simple yet effective design strategy opens up a new avenue to manufacture multifunctional materials and devices with desirable features and structural complexities for applications in sustainable antifouling, drag reduction, non-destructive transportation, liquid collection, and biomedicine, among other areas. This article is protected by copyright. All rights reserved.

Keywords:  anti-crude oil-adhesion; bendability; durability; fluorine-free coating; strong bonding force

DOI:  https://doi.org/10.1002/adma.202204581
ACS Appl Mater Interfaces. 2022 Aug 24.

Albumin-Coated Framework Nucleic Acids as Bionic Delivery System for Triple-Negative Breast Cancer Therapy.

Yuxin Zhang, Chenchen Mao, Yuxi Zhan, Yuxuan Zhao, Ye Chen, Yunfeng Lin.

  Triple-negative breast cancer (TNBC) is a subtype of breast cancer, and it has aggressive and more frequent tissue metastases than other breast cancer subtypes. Because the proliferation of TNBC tumor cells does not depend on estrogen receptor (ER), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2) and lacks accurate drug targets, conventional chemotherapy is challenging to be effective, and adverse reactions are severe. At present, the treatment strategy for TNBC generally depends on a combination of surgery, radiotherapy, and chemotherapy. Conventional administration methods have minimal effects on TNBC and cause severe damage to normal tissues. Therefore, it is an urgent task to develop an efficient and practical way of drug delivery and open up a new horizon of targeted therapy for TNBC. In our work, bovine serum albumin (BSA) acted as the protective film to prolong the circulation time of the tetrahedral framework nucleic acid (tFNA) delivery system and resist immune clearance in vivo. tFNA was used as a carrier loaded with DOX and AS1411 aptamers for the targeted treatment of triple-negative breast cancer. Compared with existing approaches, this optimized system exhibits stronger tumor-targeting so that tFNAs can be more concentrated around the tumor tissue, reducing DOX toxicity to other organs. This bionic delivery system exhibited effective tumor growth inhibition in the TNBC mice model, offering the clinical potential to promote the treatment of TNBC with great potential for clinical translation.

Keywords:  albumin; drug delivery system; long circulation; tetrahedral framework nucleic acid; triple-negative breast cancer

DOI:  https://doi.org/10.1021/acsami.2c10612
Biomaterials. 2022 Aug 12. pii: S0142-9612(22)00345-3. [Epub ahead of print] 121705

Programmed prodrug breaking the feedback regulation of P-selectin in plaque inflammation for atherosclerotic therapy.

Quan Wang, Hongshu Jing, Jun Lin, Zhihua Wu, Yu Tian, Ke Gong, Qianqian Guo, Xupeng Yang, Liting Wang, Zhaojun Li, Yourong Duan.

  Inflammation is the main driver of the aggravation of arteriosclerosis, and the complex inflammatory response in plaque is usually the result of the interaction of various cells and cytokines. Therefore, it is difficult to comprehensively regulate the inflammatory process of arteriosclerosis by intervening a single target, resulting in the poor effect of existing treatment method. Based on our clinical findings that P-selectin stably and highly expressed in patients' plaque endothelial cells, the programmed prodrug, low molecular weight heparin-indomethacin nanoparticles (LI NPs), were established as anti-inflammatory agent to multiphase inhibit arteriosclerosis by cascade interference of P-selectin. Structurally, LI NPs was obtained by simple esterification of low molecular weight heparin and indomethacin without any additives, guaranteeing the biocompatibility and applicability of LI NPs. Functionally, LI NPs could interfere with P-selectin in the inflammatory process, such as inhibiting macrophage adhesion, reducing the secretion of inflammatory factors, and inducing macrophage apoptosis. In the arteriosclerosis mice model, LI NPs significantly reduced the plaque area and showed satisfactory curative effect, which is related to the intervention of the multiphase inflammation between endothelial cells and macrophages. In conclusion, the programmed prodrug LI NPs offered a promising approach for the clinical therapy of arteriosclerosis.

Keywords:  Anti-Arteriosclerosis nanoparticles; Indomethacin; Low molecular weight heparin; P-selectin; Prodrug

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121705