Essays in biochemistry最新文献

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense extracellular matrix (ECM) and a uniquely immunosuppressive tumor microenvironment (TME), which together form a formidable barrier that hinders deep drug penetration, limiting the efficacy of conventional therapies and leading to poor patient outcomes. Nanocarrier technology emerges as a promising strategy to improve treatment efficacy in PDAC. Nanocarriers can not only improve drug penetration through their adjustable physicochemical properties but also effectively regulate immune cell function in pancreatic cancer TME and promote anti-tumor immune response. This mini-review discusses the effects of nanocarriers on the immune microenvironment of PDAC, analyzing their mechanisms in modulating immune cells, overcoming ECM barriers, and reshaping the TME.

Cellular immunotherapy has transformed cancer treatment by harnessing T cells to target malignant cells. However, its broader adoption is hindered by challenges such as efficacy loss, limited persistence, tumor heterogeneity, an immunosuppressive tumor microenvironment (TME), and safety concerns related to systemic adverse effects. Optogenetics, a technology that uses light-sensitive proteins to regulate cellular functions with high spatial and temporal accuracy, offers a potential solution to overcome these issues. By enabling targeted modulation of T cell receptor signaling, ion channels, transcriptional programming, and antigen recognition, optogenetics provides dynamic control over T cell activation, cytokine production, and cytotoxic responses. Moreover, optogenetic strategies can be applied to remodel the TME by selectively activating immune responses or inducing targeted immune cell depletion, thereby enhancing T cell infiltration and immune surveillance. However, practical hurdles such as limited tissue penetration of visible light and the need for cell- or tissue-specific gene delivery must be addressed for clinical translation. Emerging solutions, including upconversion nanoparticles, are being explored to improve light delivery to deeper tissues. Future integration of optogenetics with existing immunotherapies, such as checkpoint blockade and adoptive T cell therapies, could improve treatment specificity, minimize adverse effects, and provide real-time control over immune responses. By refining the precision and adaptability of immunotherapy, optogenetics promises to further enhance both the safety and efficacy of cancer immunotherapy.

Immune regulation is recognized as a cornerstone therapeutic strategy for the treatment of various autoimmune diseases. These disorders, driven by dysregulated immune responses, contribute significantly to morbidity and mortality. Although conventional immunosuppressive therapies provide symptomatic relief, their prolonged use is often associated with severe adverse effects, underscoring the need for safer and more effective treatment approaches. Extracellular vesicles (EVs), derived from immunoregulatory cells such as regulatory T cells, dendritic cells, mesenchymal stem cells, and neutrophils, have emerged as promising candidates for targeted immunomodulation. These nanoscale vesicles inherit the immunosuppressive properties of their parental cells, thereby facilitating immune homeostasis while mitigating the risks associated with other cell-based therapies. This review provides a comprehensive overview of recent advances in the application of immunoregulatory cell-derived EVs for autoimmune disease treatment, with a particular focus on their mechanisms of action within the immune microenvironment. Finally, we discuss the challenges and potential future directions in the development of EV-based therapies for autoimmune diseases.

Extracellular vesicles (EVs), secreted by all cellular organisms, are pivotal mediators of intercellular communication. By transporting biologically active cargos such as proteins, lipids, and nucleic acids, EVs facilitate transfer of molecular signals, effectively reflecting the characteristics of their parent cells. Immune cellderived EVs (iEVs) play a crucial role in the activation and regulation of both adaptive and innate immune responses. In the context of immune activation, iEVs drive immune cell development and activation, as well as enhance antigen presentation through both direct and cross-dressing mechanisms. Furthermore, iEVs act as signaling entities within immunological synapses, significantly amplifying immune response efficiency. In immune regulation, iEVs modulate the expression of immune checkpoint (IC) molecules and sustain immune homeostasis by transporting immunosuppressive cytokines and microRNAs, thereby mitigating excessive immune reactions. Nevertheless, the mechanistic underpinnings of iEV-mediated immune cell activation, antigen presentation, and immunoregulation remain inadequately explored. This review provides a comprehensive overview of the functions of iEVs from diverse immune cell origins and underlying mechanisms. It also examines cutting-edge engineering strategies targeting iEVs and their parent cells, while discussing their promising applications in oncology and immune-related diseases. These insights lay the foundation for the rational development of next-generation immunotherapies. While promising, the clinical translation of iEVs is hindered by low yield, high batch-to-batch variability, and insufficient targeting efficiency. The final section discusses key challenges and potential solutions.

The intricate regulation of the immune system, maintaining equilibrium between pathogen defense and self-tolerance, is fundamental to health. Disruptions in this delicate balance underlie a vast spectrum of human diseases, extending beyond oncology to encompass autoimmune disorders, chronic inflammatory conditions, infectious diseases, allergies, and hypertension. While traditional therapies often rely on broad immunosuppression or direct pathogen eradication, the rapidly evolving field of immunomodulation offers a nuanced alternative: precisely calibrating immune responses to restore homeostasis or achieve targeted defense. This special issue comprises 12 review articles contributed by 57 international researchers, synthesizing key advances and emerging strategies for harnessing immunomodulation across diverse therapeutic applications.

The swift advancement of single-cell RNA sequencing (scRNA-seq) technology has furnished a crucial instrument for investigating the tumor microenvironment (TME) and its response to immunotherapy. As immunotherapy becomes increasingly prevalent, the challenge of accurately predicting its efficacy has emerged as a prominent focus in contemporary research. In recent years, the utilization of scRNA-seq in the context of immunotherapy has demonstrated promising potential, particularly in the realms of efficacy prediction and biomarker discovery. The heterogeneity of immune cells within the TME exerts intricate and multifaceted influences on treatment response, necessitating comprehensive investigation. Furthermore, the integration of biomaterials into tumor immunotherapy presents novel research opportunities in this domain. scRNA-seq technology offers a systematic approach to evaluating the modifications in the TME induced by biomaterials. This article aims to review the current state of scRNA-seq in the context of immunotherapy, identify existing challenges within related research, and propose future research directions.

Vaccination remains a cornerstone in preventing infectious diseases and managing outbreaks. The COVID-19 pandemic has underscored the revolutionary impact of mRNA vaccine technology, which utilizes pathogenderived genomic sequences to generate specific antigens. This process involves in vitro transcription of mRNA, encoding target antigens that are subsequently encapsulated within lipid nanoparticles (LNPs) for efficient delivery into host cells. Once internalized, the mRNA enables antigen expression, triggering a robust immune response. This platform dramatically accelerates vaccine development timelines and offers unparalleled adaptability, making mRNA vaccines particularly advantageous in addressing emerging infectious diseases. The clinical success of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) has fueled broader applications, including influenza, respiratory syncytial virus (RSV), Zika, and HIV. Notably, mRNA-1345 became the first FDA-approved RSV mRNA vaccine, while self-amplifying RNA and multivalent vaccines are advancing in trials. However, CureVac's CVnCoV failed due to lack of nucleoside modifications, and mRNA-1325 (Zika) showed poor immunogenicity. Additionally, mRNA-1365 (RSV) faced an FDA clinical hold due to safety concerns. These cases highlight the need for continued optimization in sequence design, delivery, and safety assessment. Despite advancements, a key hurdle persists, including mRNA instability, ultra-low storage requirements, and LNP liver accumulation. Innovations such as lyophilization and selective organ targeting technology are being explored to improve stability extrahepatic delivery. This review examines mRNA vaccine optimization strategies, clinical progress, and challenges, providing insights into future developments in this evolving field.

Metal ions are essential elements in biological processes and immune homeostasis. They can regulate cancer cell death through multiple distinct molecular pathways and stimulate immune cells implicated in antitumor immune responses, suggesting opportunities to design novel metal ion-based cancer therapies. However, their small size and high charge density result in poor target cell uptake, uncontrolled biodistribution, and rapid clearance from the body, reducing therapeutic efficacy and increasing potential off-target toxicity. Metal coordination polymer nanoparticles (MCP NPs) are nanoscale polymer networks composed of metal ions and organic ligands linked via noncovalent coordination interactions. MCP NPs offer a promising nanoplatform for reshaping metal ions into more drug-like formulations, improving their in vivo pharmacological performance and therapeutic index for cancer therapy applications. This review provides a comprehensive overview of the inherent biological functions of metal ions in cancer therapy, showcasing examples of MCP NP systems designed for preclinical cancer therapy applications where drug delivery principles play a critical role in enhancing therapeutic outcomes. MCP NPs offer versatile metal ion engineering approaches using selected metal ions, various organic ligands, and functional payloads, enabling on-demand nano-drug designs that can significantly improve therapeutic efficacy and reduce side effects for effective cancer therapy.

The emergence of immunotherapy has led to the clinical approval of several related drugs. However, their efficacy against solid tumors remains limited. As the hub of immune activation, lymph nodes (LNs) play a critical role in tumor immunotherapy by initiating and amplifying immune responses. Nevertheless, the intricate physiological structure and barriers within LNs, combined with the immunosuppressive microenvironment induced by tumor cells, significantly impede the therapeutic efficacy of immunotherapy. Engineered nanoparticles (NPs) have shown great potential in overcoming these challenges by facilitating targeted drug transport to LNs and directly or indirectly activating T cells. This review systematically examines the structural features of LNs, key factors influencing the targeting efficiency of NPs, and current strategies for remodeling the immunosuppressive microenvironment of LNs. Additionally, it discusses future opportunities for optimizing NPs to enhance tumor immunotherapy, addressing challenges in clinical translation and safety evaluation.

Bacterial outer membrane vesicles (OMVs), naturally released by Gram-negative bacteria, are a type of lipid bilayer nanoparticles containing many components found within the parent bacterium. Despite OMVs were first considered mere by-products of bacterial growth, recent studies have shown them as a highly adaptable platform for tumor vaccine. Here, we first demonstrate the biogenesis of OMVs, then review the strong immunogenicity of OMVs as an immune adjuvant in tumor vaccine and its excellent vaccine delivery capability, and finally discuss OMVs' engineering potentials through summarizing recent scientific advancements in genetic engineering, chemical modification, and nanotechnology. We also point out the clinical trials and future challenges of OMV-based vaccine. Overall, this review offers valuable insights into cancer immunotherapy, providing a roadmap for leveraging OMVs as a versatile platform for next-generation cancer vaccines.