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Abstract Breast cancer is the most common malignant tumor that threatens women’s life and health, and metastasis often occurs in the advanced stage of breast cancer, leading to pathological bone destruction and seriously reducing patient quality of life. In this study, we coupled chlorin e6 (Ce6) with mono-(6-amino-6-deoxy)-beta-cyclodextrin (β-CD) to form Ce6-CD, and combined ferrocene with the FFVLG3C peptide and PEG chains to form the triblock molecule Fc-pep-PEG. In addition, the IDO-1 inhibitor NLG919 was loaded with Ce6-CD and Fc-pep-PEG to construct the supramolecular nanoparticle NLG919@Ce6-CD/Fc-pep-PEG (NLG919@CF). After laser irradiation, Ce6 produced robust reactive oxidative species to induce tumor cell apoptosis. Simultaneously, ferrocene became charged, and Fc-pep-PEG dissociated from the spherical nanoparticles, enabling their transformation into nanofibers, which increased both the retention effect and the induction of ferroptosis. The released NLG919 reduced the number of regulatory T cells (Tregs) and restored the function of cytotoxic T lymphocytes (CTLs) by inhibiting the activity of IDO-1. Moreover, combined administration with an anti-PD-1 antibody further relieved immune suppression in the tumor microenvironment. This article presents a new strategy for the clinical treatment of breast cancer with bone metastasis and osteolysis. Graphical Abstract

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H+ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to human clinical trials is a crucial part of drug development, which deserves greater emphasis to reduce the cost and time in drug discovery. Recent advances in microfabrication and tissue engineering have given rise to organ-on-a-chip, an in vitro model capable of recapitulating human organ functions in vivo and providing insight into disease pathophysiology, which offers a potential alternative to animal models for more efficient pre-clinical screening of drug candidates. In this review, we first give a snapshot of general considerations for organ-on-a-chip device design. Then, we comprehensively review the recent advances in organ-on-a-chip for drug screening. Finally, we summarize some key challenges of the progress in this field and discuss future prospects of organ-on-a-chip development. Overall, this review highlights the new avenue that organ-on-a-chip opens for drug development, therapeutic innovation, and precision medicine.

Acne vulgaris is one of the most prevalent skin conditions, affecting almost all teenagers worldwide. Multiple factors, including the excessive production of sebum, dysbiosis of the skin microbiome, disruption of keratinization within hair follicles, and local inflammation, are believed to trigger or aggravate acne. Immune activity plays a crucial role in the pathogenesis of acne. Recent research has improved our understanding of the immunostimulatory functions of microorganisms, lipid mediators, and neuropeptides. Additionally, significant advances have been made in elucidating the intricate mechanisms through which cutaneous innate and adaptive immune cells perceive and transmit stimulatory signals and initiate immune responses. However, our understanding of precise temporal and spatial patterns of immune activity throughout various stages of acne development remains limited. This review provides a comprehensive overview of the current knowledge concerning the immune processes involved in the initiation and progression of acne. Furthermore, we highlight the significance of detailed spatiotemporal analyses, including analyses of temporal dynamics of immune cell populations as well as single-cell and spatial RNA sequencing, for the development of targeted therapeutic and prevention strategies.

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

Abstract Cancer treatment by inducing tumor cell immunogenic cell death (ICD) is critical for tumor therapy. However, ICD activation by single pathway is often limited in practical application due to its low efficiency. In addition, the low pH and anoxic microenvironments in solid tumors greatly limit the effective activation of ICD. Herein, hollow manganese dioxide (H-MnO2) nanomaterials were selected to load both Mitoxantrone (MTZ) and Chlorin e6 (Ce6) due to its hollow structure and ability to release drugs in the acidic environments. Thus, the synergy of photodynamic therapy (PDT), photothermal therapy (PTT) and chemotherapy can induce the process of immunogenic cell death, stimulate the maturation of dendritic cells (DCs), and activate the immune response to kill tumor cells dramatically. Efficient immunotherapeutic effects were obtained when MnO2-C/M-HA was given intravenously to 4T1 tumor-bearing BALB/c mice with 660 nm near-infrared laser irradiation. This study overcame the limitations of monotherapy and provided a multifunctional platform for tumor immunotherapy.

Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO2-x) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO2-x to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90α (HSP90α), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO2-x demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

Abstract The blood–brain barrier (BBB) is a highly regulated and efficient barrier that controls the mass transfer between blood and brain, severely limits brain penetration of systemically administered therapeutics. During the onset and progression of brain tumors, BBB alters, and the blood–brain tumor barrier (BBTB) forms. Though BBTB differs from BBB in certain aspects, such as neuronal connections and aberrant pericyte distribution, it retains critical aspects of BBB. Hence, one major challenge in the development of therapeutics for brain tumor is to achieve sufficient BBTB penetration thus improving the efficiency of drug delivery to the tumor site. In this review, we summarize the strategies that can overcome BBTB and improve BBTB penetration efficiency from the perspectives of regulating BBTB structure and transport processes.

This paper studies the problem of target control and how a virtual ellipsoid can avoid the static obstacle. During the motion to the target set, the virtual ellipsoid can achieve a motion under collision avoidance by keeping the distance between the ellipsoid and obstacle. We present solutions to this problem in the class of closed-loop (feedback) controls based on Hamilton–Jacobi–Bellman (HJB) equation. Simulation results verify the validity and effectiveness of our algorithm.

The microneedle (MN), a highly efficient and versatile device, has attracted extensive scientific and industrial interests in the past decades due to prominent properties including painless penetration, low cost, excellent therapeutic efficacy, and relative safety. The robust microneedle enabling transdermal delivery has a paramount potential to create advanced functional devices with superior nature for biomedical applications. In this review, a great effort has been made to summarize the advance of microneedles including their materials and latest fabrication method, such as three-dimensional printing (3DP). Importantly, a variety of representative biomedical applications of microneedles such as disease treatment, immunobiological administration, disease diagnosis and cosmetic field, are highlighted in detail. At last, conclusions and future perspectives for development of advanced microneedles in biomedical fields have been discussed systematically. Taken together, as an emerging tool, microneedles have showed profound promise for biomedical applications. Key words: Microneedle patches, Biomedical applications, Microfabricated device, Drug delivery, Disease treatment, Disease diagnosis, Immunobiological administration, 3D printing

Background/Aims: The prevalence of hyperlipidemia is increasing rapidly. The role of Coreopsis tinctoria (CT) in amending lipid metabolism in hyperlipidemia patients has not been reported. This study aims to evaluate the role of CT in altering lipid metabolism in hyperlipidemia patients and to explore the possible mechanisms mediated by gut microbiota in hyperlipidemia mice models. Methods: A retrospective analysis in 40 hyperlipidemia patients was conducted, in which 20 patients took fenofibrate and another 20 patients normatively drank water with CT. Hyperlipidemia mice models were also established. Blood biochemical tests were performed using an automatic biochemical analyzer. Liver histopathology was observed by hematoxylin and eosin staining. Ileocecal samples were collected from mice, and bacterial DNA was extracted and sequenced by MiSeq sequencing. Bacterial composition and differences were analyzed. Results: In hyperlipidemia patients, CT was associated with decreased triglyceride and low-density lipoprotein (LDL) levels without liver injury. The experimental hyperlipidemia model also verified a similar result. Gut microbial richness and diversity were significantly decreased in hyperlipidemic mice, but increased after CT treatment. Bacterial communities were significantly differentiated between normal controls and hyperlipidemic mice. CT administration improved gut microbiota composition to an approximately normal status. Meanwhile, CT administration attenuated bacterial alterations at the class, order, family, and genus levels in hyperlipidemic mice. Importantly, the genera Barnesiella, Lactobacillus, and Helicobacter achieved high discriminatory power in hyperlipidemic mice relative to normal controls. Conclusions: CT can modulate blood lipid metabolism with improvement of liver function by decreasing LDL and improving gut microbiota compositions. These findings may provide novel therapeutic strategies for patients with hyperlipidemia.

Abstract Magnetoplasmonics, combining magnetic and plasmonic functions, has attracted increasing attention owing to its unique magnetic and optical properties in various nano-architectures. In this work, Ag, CoFeB and ITO layers are fabricated on anodic aluminum oxide (AAO) porous films to form hybrid multi-layered nanoporous thin films by magnetron sputtering deposition process. The designed nanostructure supports localized surface plasmon resonance (LSPR) and tunable magneto-optical (MO) activity, namely, the sign inversion, which can be controlled by AAO porous film geometry (pore diameter and inter-pore spacing) flexibly. The physical mechanism of this special MO phenomena is further analyzed and discussed by the correlation of Kerr rotation and electronic oscillations controlled by the surface plasmon resonance that is related to the nanoporous structure.

Strong nonlinear resistance has been found in the charge ordered ferroelectric iron oxyborate (Fe2OBO3) with a high dielectric constant and giant converse magnetoelectric effect. In low temperature range the I-V nonlinearity increases quickly with decreasing temperature. Transport measurements on polycrystalline and single crystal Fe2OBO3 indicate that the nonlinearity is not induced by grain boundaries. The nonlinear I-V behavior is intrinsically correlated with the charge order phase melting in Fe2OBO3 by detailed in-situ TEM investigations. These results provide an insight into structure-activity relationship of resistance switching effects at atomic and electric scales, which is essential for its potential application as varistors and storage media.

A highly selective imprinted amino-functionalized Fe 3 O 4 @SiO 2 sorbent was prepared by surface molecular imprinting technique for selective removal of trace 2,4-dichlorophenol (2,4-DCP) in water samples. The 2,4-DCP-imprinted amino-functionalized Fe 3 O 4 @SiO 2 sorbent was characterized by Fourier transform infrared, transmission electron microscopy, vibrating sample magnetometer, thermogravimetric analysis and batch-mode binding studies. The imprinted functionalized Fe 3 O 4 @SiO 2 sorbent exhibited high selectivity and offered a fast kinetics for the adsorption of 2,4-DCP. The prepared sorbent was shown to be promising for selective removal of trace levels of 2,4-DCP in environmental water samples.

The freeze-dried biomass of Paecilomyces lilacinus was employed as a biosorbent for the removal of silver ions from aqueous solution. The effects of factors such as the solution pH, the initial Ag(I) ion concentration, contact time and temperature were examined. Maximum Ag(I) adsorption was obtained at pH 3.0. The pseudo-first-order, pseudo-second-order and intra-particle diffusion kinetic models were fitted to the experimental data when it was found that such data were best fitted by the pseudo-second-order kinetic model. The equilibrium experimental data were well fitted by the Langmuir model (R 2 > 0.995) and the maximum biosorption capacity at 298 K was 101.0 mmol/g. Thermodynamic parameters such as the Gibbs' free energy, ΔG 0 , the standard enthalpy, ΔH 0 , and the standard entropy, ΔS 0 , were evaluated. The results indicated that the biosorption of Ag(I) ions onto P. lilacinus biomass was spontaneous and endothermic in nature. The FT-IR analysis results indicated that amine, carboxylic and hydroxyl groups were involved in the biosorption process.

Cyclin A(2) is critical for the initiation of DNA replication, transcription and cell cycle regulation. Cumulative evidences indicate that the deregulation of cyclin A(2) is tightly linked to the chromosomal instability, neoplastic transformation and tumor proliferation. Here we report that treatment of chronic myelogenous leukaemia K562 cells with doxorubicin results in an accumulation of cyclin A(2) and follows by induction of apoptotic cell death. To investigate the potential preclinical relevance, K562 cells were transiently transfected with the siRNA targeting cyclin A(2) by functionalized single wall carbon nanotubes. Knocking down the expression of cyclin A(2) in K562 cells suppressed doxorubicin-induced growth arrest and cell apoptosis. Upon administration with doxorubicin, K562 cells with reduced cyclin A(2) showed a significant decrease in erythroid differentiation, and a small fraction of cells were differentiated along megakaryocytic and monocyte-macrophage pathways. The results demonstrate the pro-apoptotic role of cyclin A(2) and suggest that cyclin A(2) is a key regulator of cell differentiation. To the best of our knowledge, this is the first report that knocking down expression of one gene switches differentiation pathways of human myeloid leukemia K562 cells.