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Yao Wang,1,* Mingtang Zeng,1,* Tianfei Fan,1 Ming Jia,2 Ruxi Yin,1 Jia Xue,1 Longjun Xian,3 Ping Fan,1 Mei Zhan1 1Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Nanchong Institute for Food and Drug Control, Nanchong, People’s Republic of China; 3Department of Thoracic Surgery, Institute of Thoracic Oncology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Fan; Mei Zhan, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email m13980602288@163.com; mandyzhanmei@163.comAbstract: Metal-organic frameworks (MOFs) are porous materials resulting from the coordination of metal clusters or ions with organic ligands, merging macromolecular and coordination chemistry features. Among these, zeolitic imidazolate framework-8 (ZIF-8) stands out as a widely utilized MOF known for its robust stability in aqueous environments owing to the robust interaction between its constituent zinc ions (Zn2+) and 2-methylimidazole (2-MIM). ZIF-8 readily decomposes under acidic conditions, serving as a promising candidate for pH-responsive drug delivery systems. Moreover, biomimetic materials typically possess good biocompatibility, reducing immune reactions. By mimicking natural structures or surface features within the body, they enhance the targeting of nanoparticles, prolong their circulation time, and increase their bioavailability in vivo. This review explores the latest advancements in biomimetic ZIF-8 nanoparticles for drug delivery, elucidating the primary obstacles and future prospects in utilizing ZIF-8 for drug delivery applications.Keywords: MOF, ZIF-8, cell membrane, biomimetic drug delivery

Junxian Ren,1,* Rongcheng Yu,1,* Jingyan Xue,1 Yiqi Tang,1 Sihui Su,1 Chenxi Liao,1 Quanyi Guo,2 Weimin Guo,3 Jinxuan Zheng1 1Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China; 2Institute of Orthopedics, Chinese PLA General Hospital, Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, People’s Republic of China; 3Department of Orthopedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weimin Guo, Department of Orthopedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People’s Republic of China, Tel +86 20 87755766#6236, Email guowm5@mail.sysu.edu.cn Jinxuan Zheng, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuan West Road, Guangzhou, 510055, People’s Republic of China, Tel +86 20 83802802, Email zhengjx27@mail.sysu.edu.cnAbstract: The maintenance of bone homeostasis includes both bone resorption by osteoclasts and bone formation by osteoblasts. These two processes are in dynamic balance to maintain a constant amount of bone for accomplishing its critical functions in daily life. Multiple cell type communications are involved in these two complex and continuous processes. In recent decades, an increasing number of studies have shown that osteogenic and osteoclastic extracellular vesicles play crucial roles in regulating bone homeostasis through paracrine, autosecretory and endocrine signaling. Elucidating the functional roles of extracellular vesicles in the maintenance of bone homeostasis may contribute to the design of new strategies for bone regeneration. Hence, we review the recent understandings of the classification, production process, extraction methods, structure, contents, functions and applications of extracellular vesicles in bone homeostasis. We highlight the contents of various bone-derived extracellular vesicles and their interactions with different cells in the bone microenvironment during bone homeostasis. We also summarize the recent advances in EV-loaded biomaterial scaffolds for bone regeneration and repair.Keywords: bone, homeostasis, metabolism, extracellular vesicles, regeneration

Junshuai Xue,1 Nianfeng Sun,2 Yang Liu3 1Department of General Surgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, People’s Republic of China; 2Women’s and Children’s Hospital Affiliated to Qingdao University, Qingdao, 266001, People’s Republic of China; 3Department of General Surgery, Vascular Surgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, People’s Republic of ChinaCorrespondence: Nianfeng Sun; Yang Liu, Tel +86 18561810688 ; +86 18560088317, Email sunnianfeng@126.com; liuyang_sdu@126.comBackground: Non-healing skin wounds are a common complication in diabetic patients. Vector biomaterials embedded with mesenchymal stem cells (MSCs) are considered a promising treatment approach. In this study, we presented a novel and effective approach to accelerate diabetic skin wound healing.Methods and Materials: Human umbilical cord mesenchymal stem cells (hUC-MSCs) were shaped into spheres. RADA16-I, KLT, and RGD nanopeptides were selected for self-assembly into hydrogels. hUC-MSCs spheroids (hUC-MSCsp) were combined in vitro with self-assembled nanopeptide hydrogels and subsequently transplanted into a mouse model of diabetic skin trauma.Results: Compared with the PBS, hUC-MSCs, hUC-MSCsp, and hUC-MSCs with hydrogel groups, hUC-MSCsp with hydrogel significantly accelerated wound healing (p< 0.01) and shortened the healing time (10 vs 14 vs 21 days). The expressions of IL-6, IL-10, IL-1β, and TNF-α were significantly decreased (p< 0.001). The expression of VEGF was significantly higher in the hUC-MSCsp with hydrogel group (p< 0.05), and the density of neovascularization in the fresh skin tissue at the wound was also remarkably increased (p< 0.01).Conclusion: Nanopeptide hydrogels loaded with hUC-MSCsp accelerated diabetic skin wound healing by inhibiting inflammation and promoting angiogenesis compared with conventional stem cell transplantation, which deserves further investigation.Keywords: diabetic wound, human umbilical cord mesenchymal stem cell, spheroid, nanopeptide hydrogels, treatment

Xingran Du,1,* Jianpeng Xue,2,* Mingzi Jiang,3 Shaoqing Lin,4 Yuzhen Huang,4 Kaili Deng,5 Lei Shu,5 Hanmei Xu,2 Zeqing Li,2 Jing Yao,4 Sixia Chen,4 Ziyan Shen,4 Ganzhu Feng4 1Department of Infectious Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2State Key Laboratory of Natural Medicines, The Engineering Research Center of Synthetic Polypeptide Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Kunshan, Suzhou, Jiangsu, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5Department of Respiratory Medicine, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ganzhu FengDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of ChinaTel +86-025-58509837Fax +86-025-58509994Email zhu1635253@163.comBackground: The development of vaccines is a promising and cost-effective strategy to prevent emerging multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections. The purpose of this study was to prepare a multiepitope peptide nanovaccine and evaluate its immunogenicity and protective effect in BALB/c mice.Methods: The B-cell and T-cell epitopes of Omp22 from A. baumannii were predicted using bioinformatics methods and identified by immunological experiments. The optimal epitopes were conjugated in series by 6-aminocaproic acid and chemically synthesized multiepitope polypeptide rOmp22. Then, rOmp22 was encapsulated by chitosan (CS) and poly (lactic-co-glycolic) acid (PLGA) to prepare CS-PLGA-rOmp22 nanoparticles (NPs). The immunogenicity and immunoprotective efficacy of the vaccine were evaluated in BALB/c mice.Results: CS-PLGA-rOmp22 NPs were small (mean size of 272.83 nm) with apparently spherical structures, positively charged (4.39 mV) and nontoxic to A549 cells. A high encapsulation efficiency (54.94%) and a continuous slow release pattern were achieved. Compared with nonencapsulated rOmp22, CS-PLGA-rOmp22 immunized BALB/c mice induced higher levels of rOmp22-specific IgG in serum and IFN-γ in splenocyte supernatant. Additionally, lung injury and bacterial burdens in the lung and blood were suppressed, and potent protection (57.14%-83.3%) against acute lethal intratracheal A. baumannii challenge was observed in BALB/c mice vaccinated with CS-PLGA-rOmp22.Conclusion: CS-PLGA-rOmp22 NPs elicited specific IgG antibodies, Th1 cellular immunity and protection against acute lethal intratracheal A. baumannii challenge. Our results indicate that this nanovaccine is a desirable candidate for preventing A. baumannii infection.Keywords: A. baumannii, epitope vaccine, polymeric nanoparticles, PLGA, chitosan

Jiyang Xue1 ,* Ruixiang Li2 ,* Dingding Gao,2 Fenghua Chen,3 Hongjuan Xie1 1Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China; 2Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 3Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiyang Xue; Hongjuan XieDepartment of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of ChinaTel +86-21-20261152Email xuejiyang7635@163.com; xiehongjuan@51mch.comIntroduction: Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes.Methods: AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied.Results: AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial–mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway.Conclusion: The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.Keywords: AMD3100, paclitaxel, nanoparticle, CXCL12/CXCR4 axis, ovarian cancer

Ke Zheng, 1–3 Hongyan Liu, 1 Xinxin Liu, 1 Ying Wang, 1 Linlin Li, 2 Shijie Li, 2 Jinping Xue, 2 Mingdong Huang 2 1College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong 266042, People’s Republic of China; 2College of Chemistry, Fuzhou University, Fuzhou, Fujian 350118, People’s Republic of China; 3Key Laboratory of Pharmaceutical Research for Metabolic Disease, Qingdao University of Science and Technology, Qingdao, Shandong 266042, People’s Republic of ChinaCorrespondence: Ke ZhengCollege of Chemical Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Qingdao, Shandong 266042, People’s Republic of ChinaTel +86 132 1018 5127Email zhengke_qust@163.comPurpose: Combination therapy for tumors is an important and promising strategy to improve therapeutic efficiency. This study aims at combining tumor targeting, chemo-, and photodynamic therapies to improve the anti-tumor performance.Patients and Methods: Human serum albumin (HSA), as a nontoxic and biodegradable drug carrier, was used to load hydrophobic photosensitizers (mono-substituted β-4-pyridyloxy phthalocyanine zinc, mPPZ) by a dilution-incubation-purification (DIP) strategy to form molecular complex HSA:mPPZ. This complex was cross-linked as nanoparticles, and then chemotherapy drug doxorubicin (DOX) was adsorbed into the nanoparticles to achieve combined photodynamic therapy and chemotherapy. Next, the surface of the obtained composite was modified by a tumor surface receptor (urokinase receptor) targeting agent (ATF-HSA) using a noncovalent method to obtain the final product (ATF-HSA@HSA:mPPZ:DOX nanoparticles, AHmDN).Results: AHmDN exhibited strong stability, remarkable cytotoxicity and higher uptake to tumor cells. Cell imaging analysis indicated that DOX was separated from AHmDN and uniformly distributed in cell nucleus while mPPZ localized in cytoplasm. The PDT activity of all the samples had been confirmed by the detection of intracellular ROS. In animal experiments, AHmDN was demonstrated to have a prominent tumor-targeting effect using a 3D imaging system. In addition, the enhanced antitumor effect of AHmDN in tumor-bearing mice was also been observed. Importantly, the tumor-targeting effect of such nanoparticles lasted for about 14 days after one injection.Conclusion: These albumin nanoparticles with combined functions of tumor targeting, chemotherapy and photodynamic therapy can highly enhance the anti-tumor effect. This drug delivery system can be applied to package other hydrophobic photosensitizers and chemotherapy drugs for improving therapeutic efficacy to tumors.Keywords: drug delivery system, combination therapy, phthalocyanine, doxorubicin, urokinase receptor mediated targeting

Weiguang Li, Jianpeng Xue, Hanmei Xu State Key Laboratory of Natural Medicines, The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, Department of Marine Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China Background: S-HM-3 is a tumor angiogenesis inhibitor with short half-life (25 min). In this present, TPGS/Solutol polymeric micelles was prepared to load together insoluble paclitaxel (PTX) and soluble S-HM-3, expecting to together deliver them to the tumor site with long-circulating, targeting function and combating multi-drug resistance (MDR). Materials and methods: PTX and S-HM-3 loaded TPGS/Solutol micelles (PHTSm) were prepared by the method of thin-film evaporation, and characterized by dynamic light scattering, transmission electron microscope (TEM), atomic force microscopy (AFM) and releasing properties. The anticancer effect of the polymeric micelles system was evaluated and confirmed by experiments of in vitro cell uptake study, in vivo pharmacokinetics, and pharmacodynamics studies. Results: Micelles exhibited smooth spherical morphology with 20~30 nm and low critical micelle concentration (CMC) value of 0.000124 mg/mL. Only about 30% of PTX were slowly released from micelles at 48h, which can beneficial to the long circulation in blood. The results of in vitro cell assay proved that S-HM-3 could be easier to get into MDA-MB-231 cell, and its angiogenesis inhibition ability was also enhanced after integrating into micelles. In particular, the results of in vivo studies showed that the half-life of S-HM-3 and PTX was significantly prolonged 25.27 and 5.54 folds, and their AUC0-∞ was enhanced 129.78 and 15.65 times, respectively. Meanwhile 83.05% tumor inhibition rate of PHTSm was achieved compared with 59.99% of PTX. Conclusions: TPGS and Solutol micelles hold promising potential to resolve the conundrum of combined therapy of cytotoxic drug and angiogenesis inhibitor with different physicochemical property and anticancer mechanism in clinical use. Keywords: paclitaxel, angiogenesis inhibitor, combination therapy, TPGS, Solutol, anti-multidrug resistance

Ying Wang,1,2 Ke Zheng,1 Guangshan Xuan,1 Mingdong Huang,3 Jinping Xue3 1College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China; 2Key Lab of Inorganic Synthetic and Applied Chemistry, State Key Lab Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China; 3College of Chemistry, Fuzhou University, Fuzhou, Fujian, China Purpose: Zinc phthalocyanine (ZnPc) has been applied widely in photodynamic therapy (PDT) with high ROS-production capacity and intense absorption in the near-infrared region. However, weak tumor targeting and the aggregation tendency of ZnPc seriously affect the therapeutic effect of PDT. Therefore, overcoming the aggregation of ZnPc and enhancing its antitumor effect were the purpose of this study.Methods: In this study, we first found that the aggregation behaviors of the photosensitizer ZnPc(TAP)4, ZnPc substituted by tertiary amine groups, were regulated finely by pH and that ZnPc(TAP)4 could be disaggregated gradually as the pH descended. ZnPc(TAP)4 and human serum albumin (HSA) molecules were assembled into nanoparticles (NPs) for tumor targeting. Meanwhile, the chemotherapy drug paclitaxel (Ptx) was loaded into HSA NPs together with ZnPc(TAP)4 for dual antitumor effects. HSA NPs loading both ZnPc(TAP)4 and Ptx (NP–ZnPc[TAP]4–Ptx) were characterized by particle size and in vitro release. Cytotoxicity, subcellular localization, tumor targeting, and anticancer effect in vivo were investigated respectively.Results: We found that NP–ZnPc(TAP)4–Ptx had good stability with qualifying particle size. Interestingly, ZnPc(TAP)4 was released from the NPs and the photodynamic activity enhanced in the acidic environment of tumor. In addition, NP–ZnPc(TAP)4–Ptx had prominent cytotoxicity and time-dependent subcellular localization characteristics. Through a three-dimensional animal imaging system, NP–ZnPc(TAP)4–Ptx showed much-enhanced tumor targeting in tumor-bearing mice. Above all, NP–ZnPc(TAP)4–Ptx was demonstrated to have the synergistic anticancer effect of PDT and chemotherapy.Conclusion: NP–ZnPc(TAP)4–Ptx had enhanced tumor targeting for the pH-sensitive property of ZnPc(TAP)4 and the transport function of HSA. NP–ZnPc(TAP)4–Ptx possessed a double-anticancer effect through the combination of ZnPc(TAP)4 and Ptx. This drug-delivery system may also be used to carry chemotherapy drugs other than Ptx for improving antitumor effects. Keywords: photodynamic therapy, drug-delivery system, controlled release, chemotherapy, antitumor activity, combination therapy

Yuanyuan Zheng,1 Hong Zhang,2 Yuping Hu,2 Lu Bai,1 Jingyi Xue1 1Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, People’s Republic of China; 2Department of Chemistry and Biology, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, People’s Republic of China Background: Myocardial infarction (MI) is a leading cause of death worldwide. Therefore, nanoparticles that applied for specific diagnosis of the infarcted area and/or local myocardial delivery of therapeutic agents, are highly desired. Materials and methods: Herein, we developed the MnO-based nanoparticles, with magnetic resonance (MR) and near-infrared fluorescence imaging modalities as an MR imaging contrast agent and potential drug vehicle for the detection and treatment of MI. The chemophysical characteristics, targeting ability toward infarcted myocardium, biodistribution, and biocompatibility of the MnO-based nanoparticles were studied. Results: It was found that the MnO-based dual-modal nanoparticles possess high r1 relaxivity and induced no notable in vitro or in vivo toxicity. In a rat model of MI, these nanoparticles represent a very promising MR imaging contrast agent for sensitive and specific detection of the infarcted area, more importantly, without cardiotoxicity, the major defect of conventional Mn-based contrasts. Moreover, ex vivo near-infrared fluorescence imaging indicated that the MnO nanoparticles preferentially accumulate in the infarcted myocardium, which makes them an ideal drug vehicle for MI treatment. Conclusion: In summary, the use of these MnO nanoparticles as a T1-weighted MR imaging contrast agent and potential drug vehicle to target the infarcted myocardium may provide new opportunities for accurate detection of myocardial infarct and treatment of ischemic heart diseases. Keywords: Cy5.5 conjugated MnO nanoparticles, Dual-modal nanoprobe, Near-infrared fluorescence imaging, Myocardial ischemia

Dawei Deng,* Yang Li,* Jianpeng Xue, Jie Wang, Guanhua Ai, Xin Li, Yueqing GuDepartment of Biomedical Engineering, China Pharmaceutical University, Nanjing, People’s Republic of China*These authors contributed equally to this workAbstract: Messenger RNA (mRNA), a single-strand ribonucleic acid with functional gene information is usually abnormally expressed in cancer cells and has become a promising biomarker for the study of tumor progress. Hairpin DNA-coated gold nanoparticle (hDAuNP) beacon containing a bare gold nanoparticle (AuNP) as fluorescence quencher and thiol-terminated fluorescently labeled stem–loop–stem oligonucleotide sequences attached by Au–S bond is currently a new nanoscale biodiagnostic platform capable of mRNA detection, in which the design of the loop region sequence is crucial for hybridizing with the target mRNA. Hence, in this study, to improve the sensitivity and selectivity of hDAuNP beacon simultaneously, the loop region of hairpin DNA was screened by bioinformatics strategy. Here, signal transducer and activator of transcription 5b (STAT5b) mRNA was selected and used as a practical example. The results from the combined characterizations using optical techniques, flow cytometry assay, and cell microscopic imaging showed that after optimization, the as-prepared hDAuNP beacon had higher selectivity and sensitivity for the detection of STAT5b mRNA in living cells, as compared with our previous beacon. Thus, the bioinformatics method may be a promising new strategy for assisting in the designing of the hDAuNP beacon, extending its application in the detection of mRNA expression and the resultant mRNA-based biological processes and disease pathogenesis.Keywords: molecular beacon, bioinformatics, gold nanoparticle, STAT5b mRNA, visual detection