Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of ...action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
Azobenzene is a well‐known derivative of stimulus‐responsive molecular switches and has shown superior performance as a functional material in biomedical applications. The results of multiple studies ...have led to the development of light/hypoxia‐responsive azobenzene for biomedical use. In recent years, long‐wavelength‐responsive azobenzene has been developed. Matching the longer wavelength absorption and hypoxia‐response characteristics of the azobenzene switch unit to the bio‐optical window results in a large and effective stimulus response. In addition, azobenzene has been used as a hypoxia‐sensitive connector via biological cleavage under appropriate stimulus conditions. This has resulted in on/off state switching of properties such as pharmacology and fluorescence activity. Herein, recent advances in the design and fabrication of azobenzene as a trigger in biomedicine are summarized.
Azobenzene is a well‐known derivative of stimulus‐responsive molecular switches and has shown superior performance as a functional material in biomedical applications. The results of numerous studies have led to the development of light/hypoxia‐responsive azobenzene for biomedical use. Recent advances in the design and fabrication of azobenzene as a trigger in biomedicine are summarized.
The use of boron dipyrromethene (BODIPY) in biomedicine is reviewed. To open, its synthesis and regulatory strategies are summarized, and inspiring cutting‐edge work in post‐functionalization ...strategies is highlighted. A brief overview of assembly model of BODIPY is then provided: BODIPY is introduced as a promising building block for the formation of single‐ and multicomponent self‐assembled systems, including nanostructures suitable for aqueous environments, thereby showing the great development potential of supramolecular assembly in biomedicine applications. The frontier progress of BODIPY in biomedical application is thereafter described, supported by examples of the frontiers of biomedical applications of BODIPY‐containing smart materials: it mainly involves the application of materials based on BODIPY building blocks and their assemblies in fluorescence bioimaging, photoacoustic imaging, disease treatment including photodynamic therapy, photothermal therapy, and immunotherapy. Lastly, not only the current status of the BODIPY family in the biomedical field but also the challenges worth considering are summarized. At the same time, insights into the future development prospects of biomedically applicable BODIPY are provided.
Boron dipyrromethene (BODIPY) is an outstanding fluorescent molecule, with high molar absorption coefficients and good chemical stability. Improvements in self‐assembly technology have fueled the applications of BODIPY in diagnosis and treatment. This review summarizes the molecular structure design and self‐assembly strategy of BODIPY, and its applications as a multifunctional theranostic agent in biomedical fields.
Drug resistance is a major problem in cancer treatment. Herein, the design of a dual‐responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin‐resistant tumors in a patient‐derived ...xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA‐type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction‐responsive Pt(IV) and red‐light‐responsive Ru(II) moieties. PolyPt/Ru self‐assembles into nanoparticles that are efficiently taken up by cisplatin‐resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1O2, induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1O2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drug‐resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli‐responsive multi‐metallic polymers provides a new strategy to overcome drug resistance.
A dual‐responsive Pt(IV)/Ru(II) bimetallic polymer is designed to treat drug‐resistant tumors in a patient‐derived‐xenograft (PDX) model. The polymer self‐assembles into nanoparticles, which circulate in bloodstream, accumulate at tumor sites, and are taken up by drug‐resistant cancer cells. The released cisplatin and Ru(II) complexes via intracellular reduction and light irradiation as well as photogenerated 1O2 inhibit the growth of drug‐resistant tumors.
Immunomodulation of tumor‐associated macrophages (TAMs) into tumor‐inhibiting M1‐like phenotype is a promising but challenging strategy. Cleverly, tumor cells overexpress CD47, a “don't eat me” ...signal that ligates with the signal regulatory protein alpha (SIRPα) on macrophages to escape phagocytosis. Thus, effective re‐education of TAMs into the “eat me” type and blocking the CD47‐SIRPα signaling play pivotal roles in tumor immunotherapy. Herein, it is reported that hybrid nanovesicles (hEL‐RS17) derived from extracellular vesicles of M1 macrophages and decorated with RS17 peptide, an antitumor peptide that specifically binds to CD47 on tumor cells and blocks CD47‐SIRPα signaling, can actively target tumor cells and remodel TAM phenotypes. Consequently, more M1‐like TAMs infiltrate into tumor tissue to phagocytize more tumor cells due to CD47 blockade. By further co‐encapsulating chemotherapeutic agent shikonin, photosensitizer IR820, and immunomodulator polymetformin in hEL‐RS17, an enhanced antitumor effect is obtained due to the combinational treatment modality and close synergy among each component. Upon laser irradiation, the designed SPI@hEL‐RS17 nanoparticles exert potent antitumor efficacy against both 4T1 breast tumor and B16F10 melanoma models, which not only suppresses primary tumor growth but also inhibits lung metastasis and prevents tumor recurrence, exhibiting great potential in boosting CD47 blockade‐based antitumor immunotherapy.
Hybrid nanoplatforms are designed by fusing M1 macrophage extracellular vesicles with drug‐loaded liposomes and decorating them with RS17 peptide, an antitumor peptide that specifically binds to CD47 on tumor cells and blocks CD47‐SIRPα signaling, which enables amplified CD47 blockade‐based tumor immunotherapy through combinational treatment strategy.
The site‐selective functionalization of unactivated C(sp3)−H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp3)−H alkylation of amino ...acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp3)−H bonds. Experimental studies revealed that C−H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C−H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C−H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp3)−H activation.
The site‐selective δ‐C(sp3)−H alkylation of amino acids and peptides with maleimides is enabled by a palladium catalyst. C−H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C−H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle generated by δ‐C−H activation. The selectivity can be explained by the Curtin–Hammett principle. PA=picolinamide.
Lattice structures, which are also known as architected cellular structures, have been applied in various industrial sectors, owing to their fascinated performances, such as low elastic modulus, high ...stiffness-to-weight ratio, low thermal expansion coefficient, and large specific surface area. The lattice structures fabricated by conventional manufacturing technologies always involve complicated process control, additional assembly steps, or other uncontrollable factors. Furthermore, limited types of unit cells can be used to construct lattice structures when using conventional processes. Fortunately, additive manufacturing technology, based on a layer-by-layer process from computer-aided design models, demonstrates the unique capability and flexibility and provides an ideal platform in manufacturing complex components like lattice structures, resulting in an effective reduction in the processing time to actual application and minimum of material waste. Therefore, additive manufacturing relieves the constraint of structure design and provides accurate fabrication for lattice structures with good quality. This work systematically presents an overview of conventional manufacturing methods and novel additive manufacturing technologies for metallic lattice structures. Afterward, the design, optimization, a variety of properties, and applications of metallic lattice structures produced by additive manufacturing are elaborated. By summarizing state-of-the-art progress of the additively manufactured metallic lattice structures, limitations and future perspectives are also discussed.
Two major technical challenges of magnetic hyperthermia are quantitative assessment of agent distribution during and following administration and achieving uniform heating of the tumor at the desired ...temperature without damaging the surrounding tissues. In this study, we developed a multimodal MRI/MPI theranostic agent with active biological targeting for improved magnetic hyperthermia therapy (MHT). First, by systematically elucidating the magnetic nanoparticle magnetic characteristics and the magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) signal enhancement effects, which are based on the magnetic anisotropy, size, and type of nanoparticles, we found that 18 nm iron oxide NPs (IOs) could be used as superior nanocrystallines for high performance of MRI/MPI contrast agents in vitro. To improve the delivery uniformity, we then targeted tumors with the 18 nm IOs using a tumor targeting peptide, CREKA. Both MRI and MPI signals showed that the targeting agent improves the intratumoral delivery uniformity of nanoparticles in a 4T1 orthotopic mouse breast cancer model. Lastly, the in vivo antitumor MHT effect was evaluated, and the data showed that the improved targeting and delivery uniformity enables more effective magnetic hyperthermia cancer ablation than otherwise identical, nontargeting IOs. This preclinical study of image-guided MHT using cancer-targeting IOs and a novel MPI system paves the way for new MHT strategies.
Most of the current nanoparticle‐based therapeutics worldwide failing in clinical trials face three major challenges: (i) lack of an optimum drug delivery platform with precise composition, (ii) lack ...of a method of directly monitoring the fate of a specific drug rather than using any other labelling molecules as a compromise, and (iii) lack of reliable cancer models with high fidelity for drug screen and evaluation. Here, starting from a PP2A inhibitor demethylcantharidin (DMC) and cisplatin, the design of a dual sensitive dual drug backboned shattering polymer (DDBSP) with exact composition at a fixed DMC/Pt ratio for precise nanomedicine is shown. DDBSP self‐assembled nanoparticle (DD‐NP) can be triggered intracellularly to break down in a chain‐shattering manner to release the dual drugs payload. Moreover, DD‐NP with extremely high Pt heavy metal content in the polymer chain can directly track the drug itself via Pt‐based drug‐mediated computer tomography and ICP‐MS both in vitro and in vivo. Finally, DD‐NP is used to eradicate the tumor burden on a high‐fidelity patient‐derived lung cancer model for the first time.
Dual‐drug‐backboned shattering polymeric theranostic nanomedicine that can be triggered intracellularly to break down in a chain‐shattering manner, releasing the dual‐drug payload, is developed. It can directly track the drug itself via Pt‐based drug‐mediated computer tomography and eradicate the tumor burden on a high‐fidelity patientderived lung cancer model.
Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
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