Abstract: Immunotherapy has transformed current cancer management, and it has achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing the activity of immune cells and facilitating tumor immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator of cellular energy metabolism and homeostasis, has gained growing attention in anti-tumor immunity. Metformin is usually considered as a cornerstone in diabetes management, and its role in activating the AMPK pathway has also been extensively explored in cancer therapy although the findings on its role remain inconsistent. Metformin in a nanomedicine formulation has been found to hold potential in reprogramming the immunosuppressive TME through immunometabolic modulation of both tumor and immune cells. This review elaborates the foundation and progress of immunometabolic reprogramming of the TME via metformin-based nanomedicines, offering valuable insights for the next generation of cancer therapy.

Abstract: Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration. It can cause severe pain, deformity and even amputation risk. However, existing clinical treatment methods for cartilage repair present certain deficiencies. Meanwhile, the repair effect of cartilage tissue engineering is also unsatisfactory. Cartilage organoids are multicellular aggregates with cartilage-like three-dimensional structure and function. On the one hand, cartilage organoids can be used to explore the pathogenesis of OA by constructing disease models. On the other hand, it can be used as filler for rapid cartilage repair. Extracellular matrix (ECM)-like three-dimensional environment is the key to construct cartilage organoids. Silk fibroin (SF)-based hydrogels not only have ECM-like structure, but also have unique mechanical properties and remarkable biocompatibility. Therefore, SF-based hydrogels are considered as ideal biomaterials for constructing cartilage organoids. In this review, we reviewed the studies of cartilage organoids and SF-based hydrogels. The advantages of SF-based hydrogels in constructing cartilage organoids and the iterative optimization of cartilage organoids through designing hydrogels by using artificial intelligence (AI) calculation are also discussed. This review aims to provide a theoretical basis for the treatment of OA using SF-based biomaterials and cartilage organoids.

Abstract: Biomarker-driven molecular imaging has emerged as an integral part of cancer precision radiotherapy. The use of molecular imaging probes, including nanoprobes, have been explored in radiotherapy imaging to precisely and noninvasively monitor spatiotemporal distribution of biomarkers, potentially revealing tumor-killing mechanisms and therapy-induced adverse effects during radiation treatment.

Abstract: Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.

Abstract: Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a crucial regulator of human physiology and pathology. Increasing evidence showcases a reciprocal relationship between ferroptosis and dysregulated metabolism, propagating a pathogenic vicious cycle that exacerbates pathology and human diseases, particularly metabolic disorders. Consequently, there is a rapidly growing interest in developing ferroptosis-based therapeutics. Therefore, a comprehensive understanding of the intricate interplay between ferroptosis and metabolism could provide an invaluable resource for mechanistic insight and therapeutic development. In this review, we summarize the important metabolic substances and associated pathways in ferroptosis initiation and progression, outline the cascade responses of ferroptosis in disease development, overview the roles and mechanisms of ferroptosis in metabolic diseases, introduce the methods for ferroptosis detection, and discuss the therapeutic perspectives of ferroptosis, which collectively aim to illustrate a comprehensive view of ferroptosis in basic, translational, and clinical science.

Abstract: Background: The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. Methods: The in vivo senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the in vitro model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation in vitro. RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. Results: We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8+ T cell-mediated antitumor immunity. Conclusions: TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.

Abstract: Rationale: Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease resulting from blood extravasating into the brain parenchyma. Escalation of erythrophagocytosis (a form of efferocytosis), avoiding the consequent release of the detrimental erythrocyte lysates, may be a promising target of ICH management. The ADAM17 inhibitor and liver X receptor (LXR) agonist could promote efficient efferocytosis and injury repair. Nevertheless, the poor bioavailability and restriction of the blood-brain barrier (BBB) hinder their application. Therefore, it is needed that biocompatible and smart nanoplatforms were designed and synthesized to realize effective therapy targeting erythrophagocytosis. Methods: We first assessed the synergistic effect of therapeutic GW280264X (an ADAM17 inhibitor) and desmosterol (an LXR agonist) on erythrophagocytosis in vitro . Then a pH-responsive neutrophil membrane-based nanoplatform (NPEOz) served as a carrier to accurately deliver therapeutic GW280264X and desmosterol to the damaged brain was prepared via co-extrusion. Afterwards, their pH-responsive performance was valued in vitro and targeting ability was assessed through fluorescence image in vivo. Finally, the pro-erythrophagocytic and anti-neuroinflammatory ability of the nanomedicine and related mechanisms were investigated. Results: After the synergistical effect of the above two drugs on erythrophagocytosis was confirmed, we successfully developed neutrophil-disguised pH-responsive nanoparticles to efficiently co-deliver them. The nanoparticles could responsively release therapeutic agents under acidic environments, and elicit favorable biocompatibility and ability of targeting injury sites. D&G@NPEOz nanoparticles enhanced erythrophagocytosis through inhibiting shedding of the efferocytotic receptors MERTK/AXL mediated by ADAM17 and accelerating ABCA-1/ABCG-1-mediated cholesterol efflux regulated by LXR respectively. In addition, the nano-formulation was able to modulate the inflammatory microenvironment by transforming efferocytes towards a therapeutic phenotype with reducing the release of proinflammatory cytokines while increasing the secretion of anti-inflammatory factors, and improve neurological function. Conclusions: This biomimetic nanomedicine is envisaged to offer an encouraging strategy to effectively promote hematoma and inflammation resolution, consequently alleviate ICH progression.

Abstract: Human osteogenic differentiation is a complex and well-orchestrated process which involves a plethora of molecular players and cellular processes. A growing number of studies have underlined that circular RNAs (circRNAs) play an important regulatory role during human osteogenic differentiation. CircRNAs are single-stranded, covalently closed non-coding RNA molecules that are acquiring increased attention as epigenetic regulators of gene expression. Given their intrinsic high conformational stability, abundance, and specificity, circRNAs can undertake various biological activities in order to regulate multiple cellular processes, including osteogenic differentiation. The most recent evidence indicates that circRNAs control human osteogenesis by preventing the inhibitory activity of miRNAs on their downstream target genes, using a competitive endogenous RNA mechanism. The aim of this review is to draw attention to the currently known regulatory mechanisms of circRNAs during human osteogenic differentiation. Specifically, we provide an understanding of recent advances in research conducted on various human mesenchymal stem cell types that underlined the importance of circRNAs in regulating osteogenesis. A comprehensive understanding of the underlying regulatory mechanisms of circRNA in osteogenesis will improve knowledge on the molecular processes of bone growth, resulting in the potential development of novel preclinical and clinical studies and the discovery of novel diagnostic and therapeutic tools for bone disorders.

Abstract: Regulated cell death (RCD) is considered a critical pathway in cancer therapy, contributing to eliminating cancer cells and influencing treatment outcomes. The application of RCD in cancer treatment is marked by its potential in targeted therapy and immunotherapy. As a type of RCD, PANoptosis has emerged as a unique form of programmed cell death (PCD) characterized by features of pyroptosis, apoptosis, and necroptosis but cannot be fully explained by any of these pathways alone. It is regulated by a multi-protein complex called the PANoptosome. As a relatively new concept first described in 2019, PANoptosis has been shown to play a role in many diseases, including cancer, infection, and inflammation. This study reviews the application of PCD in cancer, particularly the emergence and implication of PANoptosis in developing therapeutic strategies for cancer. Studies have shown that the characterization of PANoptosis patterns in cancer can predict survival and response to immunotherapy and chemotherapy, highlighting the potential for PANoptosis to be used as a therapeutic target in cancer treatment. It also plays a role in limiting the spread of cancer cells. PANoptosis allows for the elimination of cancer cells by multiple cell death pathways and has the potential to address various challenges in cancer treatment, including drug resistance and immune evasion. Moreover, active investigation of the mechanisms and potential therapeutic agents that can induce PANoptosis in cancer cells is likely to yield effective cancer treatments and improve patient outcomes. Research on PANoptosis is still ongoing, but it is a rapidly evolving field with the potential to lead to new treatments for various diseases, including cancer.

Abstract: Background: Factor-free biomaterial scaffolds play an increasingly important role in promoting in situ bone reconstruction and regeneration. However, the complicated and variable pathophysiological microenvironments of the injury sites under diabetic conditions, including the vicious cycle of oxidative stress and inflammatory response, impaired osteo/angiogenesis function and hyperactive osteoclastogenesis, as well as increased susceptibility to bacterial infection, may largely weaken the therapeutic potential of implanted scaffolds, leading to uncontrolled and poor outcomes of bone defect healing. Methods and Results: To tackle the aforementioned challenges, a mild photothermal-assisted multifunctional therapeutic platform (denoted as GAD/MC) that integrates copper-containing two-dimensional Ti3C2Tx MXene nanosheets, gelatin methacrylate, and alginate-graft-dopamine was proposed to achieve efficient and synergistic therapy for diabetic bone defects. Thereinto, copper-decorated MXene (MC) nanosheets were employed as both functional crosslinkers and nanofillers to participate in the construction of an interpenetrating polymer network structure through multiple covalent and noncovalent bonds, which conferred the hydrogel with advantageous traits like enhanced mechanical properties, injectability and moldability, strong bone tissue adhesion and self-healing ability, as well as excellent anti-swelling and near-infrared (NIR) photothermal conversion capabilities. On account of the NIR/pH dual-responsive properties, the resulting hydrogel system was capable of achieving the controlled and stimuli-responsive release of bioactive Cu2+, allowing on-demand delivery at the site of injury. Moreover, with the assistance of mild photothermal effects, this integrated hydrogel system demonstrated remarkable antibacterial and antioxidant properties. It effectively scavenged excessive reactive oxygen species (ROS), inhibited inflammatory responses, and promoted macrophage polarization towards the pro-healing M2 phenotype. Such characteristics were beneficial for recreating an optimized microenvironment that supported the adhesion, proliferation, migration, and differentiation of osteoblasts and endothelial cells, while concurrently inhibiting osteoclast function. In a critical-sized cranial defect model using diabetic rats, the injectable GAD/MC hydrogel system combined with on-demand mild hyperthermia further synergistically accelerated new bone formation and bone healing processes by eliminating intracellular ROS, ameliorating inflammation, orchestrating M2 macrophage polarization, promoting osteo/angiogenesis, and suppressing osteoclastogenesis. Conclusions: Overall, the constructed multifunctional injectable hydrogel system has emerged as a promising therapeutic candidate for addressing complex bone-related challenges by remodeling the disordered immune microenvironment and expediting the bone healing process.

Abstract: Lipid nanoparticles (LNPs) have emerged as a viable, clinically-validated platform for the delivery of mRNA therapeutics. LNPs have been utilized as mRNA delivery systems for applications including vaccines, gene therapy, and cancer immunotherapy. However, LNPs, which are typically composed of ionizable lipids, cholesterol, helper lipids, and lipid-anchored polyethylene glycol, often traffic to the liver which limits the therapeutic potential of the platform. Several approaches have been proposed to resolve this tropism such as post-synthesis surface modification or the addition of synthetic cationic lipids. Methods: Here, we present a strategy for achieving extrahepatic delivery of mRNA involving the incorporation of bile acids, a naturally-occurring class of cholesterol analogs, during LNP synthesis. We synthesized a series of bile acid-containing C14-4 LNPs by replacing cholesterol with bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, or lithocholic acid) at various ratios. Results: Bile acid-containing LNPs (BA-LNPs) were able to reduce delivery to liver cells in vitro and improve delivery in a variety of other cell types, including T cells, B cells, and epithelial cells. Our subsequent in vivo screening of selected LNP candidates injected intraperitoneally or intravenously identified a highly spleen tropic BA-LNP: CA-100, a four-component LNP containing cholic acid and no cholesterol. These screens also identified BA-LNP candidates demonstrating promise for other mRNA therapeutic applications such as for gastrointestinal or immune cell delivery. We further found that the substitution of cholic acid for cholesterol in an LNP formulation utilizing a different ionizable lipid, C12-200, also shifted mRNA delivery from the liver to the spleen, suggesting that this cholic acid replacement strategy may be generalizable. Conclusion: These results demonstrate the potential of a four-component BA-LNP formulation, CA-100, for extrahepatic mRNA delivery that could potentially be utilized for a range of therapeutic and vaccine applications.

Abstract: Wounds represent a grave affliction that profoundly impacts human well-being. Establishing barriers, preventing infections, and providing a conducive microenvironment constitute the crux of wound therapy. Hydrogel, a polymer with an intricate three-dimensional lattice, serves as a potent tool in erecting physical barriers and nurturing an environment conducive to wound healing. This enables effective control over exudation, hemostasis, accelerated wound closure, and diminished scar formation. As a result, hydrogels have gained extensive traction in the realm of wound treatment. Metallic nanoparticle carriers, characterized by their multifaceted responses encompassing acoustics, optics, and electronics, have demonstrated efficacy in wound management. Nevertheless, these carriers encounter challenges associated with swift clearance and nonuniform effectiveness. The hybridization of metallic nanoparticle carriers with hydrogels overcomes the shortcomings inherent in metallic nanoparticle-based wound therapy. This amalgamation not only addresses the limitations but also augments the mechanical robustness of hydrogels. It confers upon them attributes such as environmental responsiveness and multifunctionality, thereby synergizing strengths and compensating for weaknesses. This integration culminates in the precise and intelligent management of wounds. This review encapsulates the structural classifications, design strategies, therapeutic applications, and underlying mechanisms of metal nanoparticle hybrid hydrogels in the context of acute and chronic wound treatment. The discourse delves into the generation of novel or enhanced attributes arising from hybridization and how the current paradigm of wound therapy leverages these attributes. Amidst this continually evolving frontier, the potential of metal nanoparticle hybrid hydrogels to revolutionize wound treatment is underscored.

Abstract: Human organoids-on-chips (OrgOCs) are the synergism of human organoids (HOs) technology and microfluidic organs-on-chips (OOCs). OOCs can mimic extrinsic characteristics of organs, such as environmental clues of living tissue, while HOs are more amenable to biological analysis and genetic manipulation. By spatial cooperation, OrgOCs served as 3D organotypic living models allowing them to recapitulate critical tissue-specific properties and forecast human responses and outcomes. It represents a giant leap forward from the regular 2D cell monolayers and animal models in the improved human ecological niche modeling. In recent years, OrgOCs have offered potential promises for clinical studies and advanced the preclinical-to-clinical translation in medical and industrial fields. In this review, we highlight the cutting-edge achievements in OrgOCs, introduce the key features of OrgOCs architectures, and share the revolutionary applications in basic biology, disease modeling, preclinical assay and precision medicine. Furthermore, we discuss how to combine a wide range of disciplines with OrgOCs and accelerate translational applications, as well as the challenges and opportunities of OrgOCs in biomedical research and applications.

Abstract: The comprehensive management of diabetic bone defects remains a substantial clinical challenge due to the hostile regenerative microenvironment characterized by aggravated inflammation, excessive reactive oxygen species (ROS), bacterial infection, impaired angiogenesis, and unbalanced bone homeostasis. Thus, an advanced multifunctional therapeutic platform capable of simultaneously achieving immune regulation, bacterial elimination, and tissue regeneration is urgently designed for augmented bone regeneration under diabetic pathological milieu.

Abstract: Exosomes, carrying distinctive biomolecules reflective of their parent cell's status and origin, show promise as liquid biopsy biomarkers for cancer diagnosis. However, their clinical translation remains challenging due to their relatively low concentration in body fluids. Surface-Enhanced Raman spectroscopy (SERS) has recently gained significant attention as a label-free and sensitive technique for exosome analysis. This review explores label-free SERS for exosome detection, covering exosome isolation and characterization methods, advancements in SERS substrates, and fingerprint analysis techniques using machine learning. Furthermore, we emphasize the challenges and offer insights into the future prospects of SERS-based exosome analysis to enhance cancer diagnosis.

Abstract: Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive therapeutic target. In the past decade, the rapid development of various Trop2-targeted therapies, notably marked by the advent of the antibody-drug conjugate (ADC), revolutionized the outcome for patients facing Trop2-positive tumors with limited treatment opinions, such as triple-negative breast cancer (TNBC). This review provides a comprehensive summary of advances in Trop2-targeted therapies, including ADCs, antibodies, multispecific agents, immunotherapy, cancer vaccines, and small molecular inhibitors, along with in-depth discussions on their designs, mechanisms of action (MOAs), and limitations. Additionally, we emphasize the clinical research progress of these emerging Trop2-targeted agents, focusing on their clinical application and therapeutic efficacy against tumors. Furthermore, we propose directions for future research, such as enhancing our understanding of Trop2’s structure and biology, exploring the best combination strategies, and tailoring precision treatment based on Trop2 testing methodologies.

Abstract: Inflammatory bowel disease (IBD) is a chronic disorder characterized by persistent inflammation of the gastrointestinal tract. Due to the elusive causes and complex mechanisms of this disorder, the development of highly effective therapeutic drugs is crucial. Extracellular vesicles (EVs) are small membrane-bound structures released by cells into the surrounding environment. Recent research has witnessed a substantial surge in the utilization of plant-derived EVs that offer advantages such as high productivity, low production costs, diverse biological functions, and low cytotoxicity. Herein, Red cabbage-derived EVs (Rabex) were investigated and engineered as potential therapeutic agents for IBD.

Abstract: Cancer remains a severe public health burden worldwide. One of the challenges hampering effective cancer therapy is that the existing cancer models hardly recapitulate the tumor microenvironment of human patients. Over the past decade, tumor organoids have emerged as an in vitro 3D tumor model to mimic the pathophysiological characteristics of parental tumors. Various techniques have been developed to construct tumor organoids, such as matrix-based methods, hanging drop, spinner or rotating flask, nonadhesive surface, organ-on-a-chip, 3D bioprinting, and genetic engineering. This review elaborated on cell components and fabrication methods for establishing tumor organoid models. Furthermore, we discussed the application of tumor organoids to cancer modeling, basic cancer research, and anticancer therapy. Finally, we discussed current limitations and future directions in employing tumor organoids for more extensive applications.

Abstract: The integration of tumor-on-a-chip technology with mini-tissues or organoids has emerged as a powerful approach in cancer research and drug development. This review provides an extensive examination of the diverse biofabrication methods employed to create mini-tissues, including 3D bioprinting, spheroids, microfluidic systems, and self-assembly techniques using cell-laden hydrogels. Furthermore, it explores various approaches for fabricating organ-on-a-chip platforms. This paper highlights the synergistic potential of combining these technologies to create tumor-on-a-chip models that mimic the complex tumor microenvironment and offer unique insights into cancer biology and therapeutic responses.

Abstract: Background: The repair of osteoporotic bone defects remains challenging due to excessive reactive oxygen species (ROS), persistent inflammation, and an imbalance between osteogenesis and osteoclastogenesis. Methods: Here, an injectable H 2 -releasing hydrogel (magnesium@polyethylene glycol-poly(lactic-co-glycolic acid), Mg@PEG-PLGA) was developed to remodel the challenging bone environment and accelerate the repair of osteoporotic bone defects. Results: This Mg@PEG-PLGA gel shows excellent injectability, shape adaptability, and phase-transition ability, can fill irregular bone defect areas via minimally invasive injection, and can transform into a porous scaffold in situ to provide mechanical support. With the appropriate release of H 2 and magnesium ions, the 2Mg@PEG-PLGA gel (loaded with 2 mg of Mg) displayed significant immunomodulatory effects through reducing intracellular ROS, guiding macrophage polarization toward the M2 phenotype, and inhibiting the I κ B/NF-κ B signaling pathway. Moreover, in vitro experiments showed that the 2Mg@PEG-PLGA gel inhibited osteoclastogenesis while promoting osteogenesis. Most notably, in animal experiments, the 2Mg@PEG-PLGA gel significantly promoted the repair of osteoporotic bone defects in vivo by scavenging ROS and inhibiting inflammation and osteoclastogenesis. Conclusions: Overall, our study provides critical insight into the design and development of H 2 -releasing magnesium-based hydrogels as potential implants for repairing osteoporotic bone defects.

Abstract: Over the past ten years, significant advancements have been made in exploring plant-derived exosome-like nanoparticles (PELNs) for disease therapeutics and drug delivery.PELNs, as inherent nanoscale particles comprised of proteins, lipids, nucleic acids, and secondary metabolites, exhibit the capacity for cellular uptake by human cells.This intercellular interaction transcends biological boundaries, effectively influencing biological functions in animals.PELNs have outstanding biocompatibility, low immunogenicity, enhanced safety, and environmentally friendly sustainability.This article summarized the preparation methods and characteristics of PELNs.It provided a systematic review of the varied roles of PELNs derived from fruits, vegetables, and herbs in disease therapeutics and drug delivery.The challenges in their production and application were discussed, and future prospects in this rapidly evolving field were explored.

Abstract: Theranostic platforms, combining diagnostic and therapeutic approaches within one system, have garnered interest in augmenting invasive surgical, chemical, and ionizing interventions. Magnetic particle imaging (MPI) offers a quite recent alternative to established radiation-based diagnostic modalities with its versatile tracer material (superparamagnetic iron oxide nanoparticles, SPION). It also offers a bimodal theranostic framework that can combine tomographic imaging with therapeutic techniques using the very same SPION. Methods : We show the interleaved combination of MPI-based imaging, therapy (highly localized magnetic fluid hyperthermia (MFH)) and therapy safety control (MPI-based thermometry) within one theranostic platform in all three spatial dimensions using a commercial MPI system and a custom-made heating insert. The heating characteristics as well as theranostic applications of the platform were demonstrated by various phantom experiments using commercial SPION. Results : We have shown the feasibility of an MPI-MFH-based theranostic platform by demonstrating high spatial control of the therapeutic target, adequate MPI-based thermometry, and successful in situ interleaved MPI-MFH application. Conclusions : MPI-MFH-based theranostic platforms serve as valuable tools that enable the synergistic integration of diagnostic and therapeutic approaches. The transition into in vivo studies will be essential to further validate their potential, and it holds promising prospects for future advancements.

Abstract: Rationale: The therapeutic benefits of bilirubin in the treatment of ulcerative colitis (UC) are considerable, whereas the underlying mechanism of bilirubin on UC remains unclear remains unexplored. In addition, the weak hydrophilicity and toxicity have limited its translational applications. Methods: We have developed a colon dual-targeting nanoparticle, for orally delivering bilirubin through hydrogel encapsulation of hyaluronic acid (HA)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles (HA-PLGA Bilirubin ). Confocal microscopy and in vivo imaging were used to evaluate the uptake and the targeted property of HA-PLGA Bilirubin in UC

Abstract: Exosomes, which are small vesicles enclosed by a lipid bilayer and released by many cell types, are widely dispersed and have garnered increased attention in the field of regenerative medicine due to their ability to serve as indicators of diseases and agents with therapeutic potential. Exosomes play a crucial role in mediating intercellular communication through the transfer of many biomolecules, including proteins, lipids, RNA, and other molecular constituents, between cells. The targeted transport of proteins and nucleic acids to specific cells has the potential to enhance or impair specific biological functions. Exosomes have many applications, and they can be used alone or in combination with other therapeutic approaches. The examination of the unique attributes and many functions of these factors has emerged as a prominent field of study in the realm of biomedical research. This manuscript summarizes the origins and properties of exosomes, including their structural, biological, physical, and chemical aspects. This paper offers a complete examination of recent progress in tissue repair and regenerative medicine, emphasizing the possible implications of these methods in forthcoming tissue regeneration attempts.

Abstract: Recent advancements in modern science have provided robust tools for drug discovery. The rapid development of transcriptome sequencing technologies has given rise to single-cell transcriptomics and single-nucleus transcriptomics, increasing the accuracy of sequencing and accelerating the drug discovery process. With the evolution of single-cell transcriptomics, spatial transcriptomics (ST) technology has emerged as a derivative approach. Spatial transcriptomics has emerged as a hot topic in the field of omics research in recent years; it not only provides information on gene expression levels but also offers spatial information on gene expression. This technology has shown tremendous potential in research on disease understanding and drug discovery. In this article, we introduce the analytical strategies of spatial transcriptomics and review its applications in novel target discovery and drug mechanism unravelling. Moreover, we discuss the current challenges and issues in this research field that need to be addressed. In conclusion, spatial transcriptomics offers a new perspective for drug discovery.

Abstract: Aim: To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by Bifidobacterium breve (B. breve) and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Methods: Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of B. breve and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of B. breve. Efficacious molecules produced by B. breve were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. Results: B. breve alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of B. breve. Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following B. breve supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with B. breve in CAC mice and highly enriched in the culture supernatant of B. breve. Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs in vitro. The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of B. breve and ILA in relieving colitis and tumorigenesis. Conclusion: B. breve-mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.

Abstract: Outer membrane vesicles (OMVs) are nanoscale lipid bilayer structures released by gram-negative bacteria. They share membrane composition and properties with their originating cells, making them adept at traversing cellular barriers. These OMVs have demonstrated exceptional membrane stability, immunogenicity, safety, penetration, and tumor-targeting properties, which have been leveraged in developing vaccines and drug delivery systems. Recent research efforts have focused on engineering OMVs to increase production yield, reduce cytotoxicity, and improve the safety and efficacy of treatment. Notably, gastrointestinal (GI) tumors have proven resistant to several traditional oncological treatment strategies, including chemotherapy, radiotherapy, and targeted therapy. Although immune checkpoint inhibitors have demonstrated efficacy in some patients, their usage as monotherapy remains limited by tumor heterogeneity and individual variability. The immunogenic and modifiable nature of OMVs makes them an ideal design platform for the individualized treatment of GI tumors. OMV-based therapy enables combination therapy and optimization of anti-tumor effects. This review comprehensively summarizes recent advances in OMV engineering for GI tumor therapy and discusses the challenges in the clinical translation of emerging OMV-based anti-tumor therapies.

Abstract: The treatment of wounds is a worldwide challenge, and wound infection can affect the effectiveness of wound treatment and further increase the disease burden. Copper is an essential trace element that has been shown to have broad-spectrum antibacterial effects and to be involved in the inflammation, proliferation, and remodeling stages of wound healing. Compared to treatments such as bioactive factors and skin grafts, copper has the advantage of being low-cost and easily available, and has received a lot of attention in wound healing. Recently, biomaterials made by incorporating copper into bioactive glasses, polymeric scaffolds and hydrogels have been used to promote wound healing by the release of copper ions. In addition, copper-incorporated biomaterials with catalytic, photothermal, and photosensitive properties can also accelerate wound healing through antibacterial and wound microenvironment regulation. This review summarizes the antibacterial mechanisms of copper-incorporated biomaterials and their roles in wound healing, and discusses the current challenges. A comprehensive understanding of the role of copper in wounds will help to facilitate new preclinical and clinical studies, thus leading to the development of novel therapeutic tools.

Abstract: The mRNA vaccine, a groundbreaking advancement in the field of immunology, has garnered international recognition by being awarded the prestigious Nobel Prize, which has emerged as a promising prophylactic and therapeutic modality for various diseases, especially in cancer, rare disease, and infectious disease such as COVID-19, wherein successful mRNA treatment can be achieved by improving the stability of mRNA and introducing a safe and effective delivery system. Nanotechnology-based delivery systems, such as lipid nanoparticles, lipoplexes, polyplexes, lipid-polymer hybrid nanoparticles and others, have attracted great interest and have been explored for mRNA delivery. Nanoscale platforms can protect mRNA from extracellular degradation while promoting endosome escape after endocytosis, hence improving the efficacy. This review provides an overview of diverse nanoplatforms utilized for mRNA delivery in preclinical and clinical stages, including formulation, preparation process, transfection efficiency, and administration route. Furthermore, the market situation and prospects of mRNA vaccines are discussed here.