Advanced Therapeutics

Abstract Adoptive T cell therapies are transforming the treatment of solid and liquid tumors, yet their widespread adoption is limited in part by the challenge of generating functional cells. T cell activation and expansion using conventional antigen‐presenting cells (APCs) is unreliable due to the variable quality of donor‐derived APCs. As a result, engineered approaches using nanomaterials presenting T cell activation signals are a promising alternative due to their ability to be robustly manufactured with precise control over stimulation cues. Here, synthetic APCs that consist of liposomes surface‐functionalized with peptide‐major histocompatibility complexes are designed. Synthetic APCs selectively target and activate antigen‐specific T cell populations to levels similar to conventional protocols using nonspecific αCD3 and αCD28 antibodies without the need for costimulation signals. T cells treated with synthetic APCs produce effector cytokines and demonstrate cytotoxic activity when co‐cultured with tumor cells presenting target antigen in vitro. Following adoptive transfer into tumor‐bearing mice, activated cells control tumor growth and improve overall survival compared to untreated mice. Synthetic APCs can potentially be used in the future to improve the accessibility of adoptive T cell therapies by removing the need for conventional APCs during manufacturing.

Shreyas N. Dahotre

Anna M. Romanov

Fang‐Yi Su

Gabriel A. Kwong

Synthetic Antigen‐Presenting Cells for Adoptive T Cell Therapy

用于过继性T细胞治疗的合成抗原呈递细胞

Recurrence of prostate cancer after radical prostatectomy is a consequence of incomplete tumor resection. Systemic chemotherapy after surgery is associated with significant toxicity. Improved delivery methods for toxic drugs capable of targeting positive resection margins can reduce tumor recurrence and avoid their known toxicity. This study evaluates the effectiveness and toxicity of docetaxel (DTX) release from highly porous biodegradable microparticles intended for delivery into the tissue cavity created during radical prostatectomy to target residual tumor cells. The microparticles, composed of poly(dl‐lactide‐co‐glycolide) (PLGA), are processed using thermally induced phase separation (TIPS) and loaded with DTX via antisolvent precipitation. Sustained drug release and effective toxicity in vitro are observed against PC3 human prostate cells. Peritumoral injection in a PC3 xenograft tumor model results in tumor growth inhibition equivalent to that achieved with intravenous delivery of DTX. Unlike intravenous delivery of DTX, implantation of DTX‐TIPS microparticles is not accompanied by toxicity or elevated systemic levels of DTX in organ tissues or plasma. DTX‐TIPS microparticles provide localized and sustained release of nontoxic therapeutic amounts of DTX. This may offer novel therapeutic strategies for improving management of patients with clinically localized high‐risk disease requiring radical prostatectomy and other solid cancers at high risk of positive resection margins.

Ketevan Paliashvili

Alexander Popov

Tammy L. Kalber

P. Stephen Patrick

Angela Hayes

Alan Henley

Florence I. Raynaud

Hashim U. Ahmed

Richard M. Day

Peritumoral Delivery of Docetaxel‐TIPS Microparticles for Prostate Cancer Adjuvant Therapy

前列腺癌辅助治疗的紫杉醇-TIPS微粒瘤周递送

Abstract Recently, reactive oxygen species (ROS) scavenging nanozymes have been developed as natural enzyme alternatives to treat inflammatory bowel disease (IBD) as well as other inflammatory diseases. Among them, manganese oxide nanozymes are advantageous because of remarkable biocompatibility and their good biodegradability. It is herein reported that phospholipid coated Mn 3 O 4 nanozymes mimic both superoxide dismutase (SOD) and catalase (CAT) to effectively eliminate ROS that exacerbate inflammation and cause damages to tissues and organs. With the help of phospholipid decoration, the Mn 3 O 4 nanozymes are well dispersed and show good stability. Moreover, the coating enables the successful fluorescence labelling to study their biodistribution and fate. Excitingly, the Mn 3 O 4 nanozymes exhibit superior therapeutic efficacy for both ulcerative colitis (UC) and Crohn's disease (CD) in mouse models over aminosalicylic acid, a first‐line medication for IBD, under the same dosage. Thus, the Mn 3 O 4 nanozymes in this work offer a promising nano‐medication for inflammation‐related disease therapy and broaden the spectrum of biomedical application of nanozymes.

Yuan Cheng

Chaoqun Cheng

Jia Yao

Yijun Yu

Yufeng Liu

He Zhang

Leiying Miao

Hui Wei

Adv. Therap.

Mn3O4 Nanozyme for Inflammatory Bowel Disease Therapy

用于炎症性肠病治疗的Mn3O4纳米酶

Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.

Stephanie M. Kronstadt

Alex E. Pottash

Daniel Levy

Sheng Wang

Wei Chao

Steven M. Jay

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

脓毒症治疗中细胞外囊泡的潜在治疗作用

Abstract Skin injuries leading to drug‐resistant bacterial infections remain a significant challenge, posing a threat to human health. There is an urgent necessity to develop wound dressings for the treatment of such injuries. The proceeding study presents the design of a multifunctional microneedle (MNs) patch containing quorum‐quenching enzyme and manganese dioxide (MnO 2 ) nanoparticles for treating Pseudomonas aeruginosa ‐infected wounds. In co‐culture experiments with P. aeruginosa , the quorum‐quenching enzyme significantly reduced the production of virulence factors and inhibited biofilm formation. MnO 2 NPs exhibited excellent scavenging ability against a wide range of free radicals when assayed in in vitro antioxidant assays. Subsequently, soluble hyaluronic acid is chosen as the substrate in order to prepare the MNs patches loaded with quorum quenching enzyme and MnO 2 NPs for wound healing assessment in a P. aeruginosa ‐infected mouse wound model. Evaluation of wound size and closure rate demonstrated that the patch significantly accelerated wound healing, resulting in shorter healing durations and improved wound closure. Additionally, inflammation‐related cytokine levels are reduced, indicating a lower level of inflammation. Tissue section staining shows that treatment with MNs promoted wound epithelialization, collagen deposition, and angiogenesis. The multifunctional MNs patch represents a promising treatment option for drug‐resistant bacterial infections in wound management.

Binqing Xue

Yao Yao

Enhui Luo

Duncan James Lessing

Min Guo

Weihua Chu

An Integrated Therapeutic Nanoparticles and Quorum Quenching‐Based Microneedle Patch for Bacterial‐Infected Wound Healing

用于细菌感染伤口愈合的综合治疗纳米颗粒和群体感应淬灭微针贴片

Abstract Allergen‐specific immunotherapy (AIT) has demonstrated its ability to induce desensitization, resulting in reduced allergen‐specific immunoglobulin E (sIgE) accompanied by increased clinical thresholds. However, ensuring safety during therapy, especially with oral immunotherapy, and achieving long‐term tolerance continue to be significant challenges. To address these issues, a concept of nanoencapsulation of allergens has emerged. This paper reviews biodegradable and non‐biodegradable nanoparticles as an allergen‐delivery system, as well as adjuvants for the improvement of the efficacy of AIT. Of all the nanoparticles reviewed, polymethyl methacrylate (PMMA) and chitosan are the most popular nanoparticles for encapsulating macromolecular allergens for oral immunotherapy. Although poly(lactic‐co‐glycolic acid) (PLGA) demonstrates higher stability in the gastrointestinal environment and allergen‐loaded PLGA attenuates the sIgE antibody binding in a murine model, it has inconsistent loading capacity and is difficult to reproduce. Studies on biodistribution, pharmacokinetics, and pharmacodynamics of nanoparticles, however, should be highlighted to ensure the long‐term safety profile of utilizing nanoparticles in immunotherapy. In this regard, encapsulation efficiency and release behavior of allergens from nanoparticles are important components in predicting the safety and efficacy of treatments. The stability, reproducibility, and scalability of encapsulated allergens should also be considered for the translation to clinical applications.

Jiann Huey Lee

Rona Chandrawati

N. Alice Lee

Nanoparticles in Allergen‐Delivery Systems for Allergen‐Specific Immunotherapy

过敏原递送系统中纳米颗粒用于过敏原特异性免疫治疗

Abstract The bacterial pathogen, Mycobacterium tuberculosis ( Mtb ), remains a leading cause of global morbidity and mortality. Due to the complexity of the infection, the limited efficacy of antibiotics, and the increasing incidence of multi‐drug resistant strains, novel therapeutics are urgently needed. An interesting new approach is to combine antibiotics with treatments that boost the natural ability of host cells to kill the bacteria, so‐called host‐directed therapeutics (HDT). Until now, this approach has not been explored in the context of nanoparticle drug delivery, which may offer several advantages. Here, the HDT drug everolimus and the antibiotic (( S )‐2‐nitro‐6‐((5‐((4‐(trifluoromethoxy)phenyl)ethynyl)pyridin‐2‐yl)methoxy)‐6,7‐dihydro‐5 H ‐imidazo[2,1‐ b ][1,3]oxazine, drug D) are focused on. Both of these agents, drug D and everolimus, are encapsulated into one single micelle (PeptoMicelles), resulting in formulation C, and compared with micelles containing only drug D (formulation A) or everolimus (formulation B). They are tested in Mtb‐ infected primary macrophages and THP‐1 cells, and in the zebrafish model for TB ( Mm infection) using embryo survival analysis. The results show that formulation C, containing drug D and everolimus in one micelle, is significantly more efficient in protecting cells and zebrafish embryos against infection than all other formulations, indicating an improved therapeutic efficacy of HDTs and antibiotics in a single polymeric micelle.

Gabriela Schäfer

Dongdong Bi

Federico Fenaroli

Andrew M. Thompson

Anno Saris

Matthias Barz

Nanoparticles Combining Host‐Directed Therapeutics and Antibiotics to Boost Bacterial Killing and Overall Survival of Zebrafish Embryos Infected with Mycobacterium Marinum

纳米颗粒结合宿主导向治疗和抗生素以增强杀灭细菌及感染海分枝杆菌斑马鱼胚胎的整体存活率

Abstract In colorectal cancer (CRC), BRAF inhibitor (BRAFi) monotherapy appears ineffective, while cisplatin treatment is associated with adverse effects, drug resistance, and reduced efficacy. Herein, a combinatorial approach is being explored to increase the likelihood of effectively killing colorectal cancer cells. The combined effect of BRAFi (PLX4720, Vemurafenib, Dabrafenib, Encorafenib) and cisplatin treatment is examined in BRAFV600E‐mutated (RKO, HT29, Colo‐205) and BRAFwt (Caco‐2) cell lines, as well as in mouse xenografts of RKO cells. Following cisplatin‐only treatment, all cell lines show accumulation within subG1 (apoptotic cells) and G2/M phases, as well as phosphorylation of ERK1/2 and H2AX. Following BRAFi‐only treatment, BRAFV600E‐mutated cells show accumulation within G0/G1 phase, reduced distribution in the S and G2/M phases, inhibition of ERK1/2 phosphorylation, and increased phosphorylation of H2AX. Combined BRAFi and cisplatin treatment synergistically decrease RKO cells viability, reduce phosphorylation of ERK1/2, and increase phosphorylation of H2AX. Importantly, in mouse xenografts of RKO cells, combined PLX4720 and cisplatin treatment show superior therapeutic potential than each monotherapy ( P &lt; 0.001). Taken together, in in vitro and in vivo preclinical models, BRAFi and cisplatin combined treatment has shown an improved antitumor effect, rendering it a potential anticancer treatment strategy for BRAF‐mutant colon cancer patients.

Kassandra Koumaki

Salomi Skarmalioraki

Vivian Kosmidou

Lida Krikoni

Maria Goulielmaki

Vassilis Zoumpourlis

Alexander Pintzas

Vassilis L. Souliotis

Antitumorigenic Effect of Combination Treatment with BRAF Inhibitor and Cisplatin in Colorectal Cancer In Vitro and In Vivo

BRAF抑制剂与顺铂联合治疗在结直肠癌体外和体内的抗肿瘤作用

Abstract Gaucher Disease (GD) is a well‐known lysosomal storage disease resulting from mutations in the GBA1 gene. GD exhibits a range of clinical manifestations, each with unique symptoms and severity levels. This review explores the genetic foundations of GD, highlighting the significance of Glucocerebrosidase (GCase) deficiency, resulting in the skeletal complications associated with GD, such as osteonecrosis, fractures, and bone pain, all of which significantly negatively influence the quality of life for patients. Over 700 mutations in the GBA1 gene are found to cause variations in gene expression in GD, indicating the disease's complexity and the need for continued research. Early diagnosis and prognosis evaluation depend heavily on diagnostic approaches integrating laboratory assessments, genetic testing, and clinical symptoms. Treatment strategies like enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) have advanced, but issues like high costs and invasiveness still exist. This review focuses on novel therapeutic approaches that show promise in treating GD, including gene and cell‐based therapies, pharmacological chaperone therapy (PCT), and drug delivery via nanoparticles. Finally, discussions on current clinical trials, limitations of the advanced therapies, and future scope are summarized.

Lipi Pradhan

Sumit Manna

Pragya Pragya

Sudip Mukherjee

Recent Therapeutic Advancements for Gaucher Disease

戈谢病治疗进展

Abstract Tissue regeneration involves dynamic dialogue between and among different cells and their surrounding matrices. Bone regeneration is specifically governed by reciprocity between osteoblasts and osteoclasts within the bone microenvironment. Osteoclast‐directed resorption and osteoblast‐directed formation of bone are essential to bone remodeling, and the crosstalk between these cells is vital to curating a sequence of events that culminate in the creation of bone tissue. Among bone biomaterial strategies, many have investigated the use of different material cues to direct the development and activity of osteoblasts. However, less attention has been given to exploring features that similarly target osteoclast formation and activity, with even fewer strategies demonstrating or integrating biomaterial‐directed modulation of osteoblast‐osteoclast coupling. This review aims to describe various biomaterial cues demonstrated to influence osteoclastogenesis and osteoclast function, emphasizing those that enhance a material construct's ability to achieve bone healing and regeneration. Additionally discussed are approaches that influence the communication between osteoclasts and osteoblasts, particularly in a manner that takes advantage of their coupling. Deepening the understanding of how biomaterial cues may dictate osteoclast differentiation, function, and influence on the microenvironment may enable the realization of bone‐replacement interventions with enhanced integrative and regenerative capacities.

Kaavian Shariati

Meiwand Bedar

Kelly X. Huang

Shahrzad Moghadam

Sarah Mirzaie

Jonnby S. LaGuardia

Wei Chen

Youngnam Kang

Xiaoyan Ren

Justine C. Lee

Biomaterial Cues for Regulation of Osteoclast Differentiation and Function in Bone Regeneration

骨再生中调节破骨细胞分化和功能的生物材料线索

短名	Adv. Therap.
Journal Impact	3.67
国际分区	PHARMACOLOGY & PHARMACY(Q2)
期刊索引	SCI Q2中科院 4 区

ISSN	2366-3987
h-index	39
国内分区	医学(4区)医学药学(4区)

涉及主题	医学生物化学遗传学内科学生物化学材料科学物理纳米技术有机化学工程类免疫学药理学量子力学癌症研究化学工程癌症心理学计算机科学
出版信息	出版商: Wiley-Blackwell Publishing Ltd，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 2018，原创研究文献占比: 79.46%，自引率:2.70%， Gold OA占比: 25.95%

Advanced Therapeutics

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