Jutaek Nam

Hypoxic injury is a major contributor to cognitive impairment (CI), but the lipid metabolic mechanisms linking hypoxia (HYP) to hippocampal ferroptosis remain understood. This study investigated whether the arachidonate 15-lipoxygenase-cytosolic phospholipase A2 group IVC-lysophosphatidylcholine 18:0 (ALOX15-PLA2G4C-LPC18:0) axis contributes to HYP-induced hippocampal ferroptosis and CI. Morris water maze testing, Nissl staining, and NeuN immunofluorescence showed that HYP impaired spatial learning and memory and induced hippocampal neuronal loss in mice. Semi-targeted LC–MS/MS lipidomics revealed marked phospholipid/lysophospholipid (PL/LPL) remodeling, characterized by increased phosphatidylcholine and phosphatidylethanolamine species and decreased lysophosphatidylcholine species, particularly LPC18:0. Ferroptosis-related biochemical assays and transmission electron microscopy further demonstrated glutathione (GSH) depletion, malondialdehyde (MDA) accumulation, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial abnormalities. GEO dataset analysis, qRT-PCR, and Western blotting identified ALOX15 as a HYP-responsive ferroptosis-associated regulator. Hippocampal AAV-mediated Alox15 knockdown improved cognitive performance, preserved hippocampal neurons, suppressed lipid peroxidation, and partially restored PL/LPL homeostasis. In HYP-exposed SH-SY5Y cells, genetic and pharmacological experiments further supported the contribution of ALOX15 to ferroptosis-related injury. RNA sequencing, promoter-reporter assays, and gain- and loss-of-function experiments suggested that ALOX15 suppressed PLA2G4C expression partly through MAFK-dependent transcriptional modulation. PLA2G4C restoration increased LPC18:0 production, whereas LPC18:0 supplementation attenuated ferroptosis-related injury and improved hippocampal pathology and cognitive performance in HYP-exposed mice. Collectively, these findings support the ALOX15-PLA2G4C-LPC18:0 axis as a potential lipid-remodeling mechanism underlying HYP-induced hippocampal ferroptosis and highlight ALOX15 inhibition and LPC18:0 restoration as potential strategies for mitigating HYP-induced CI.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has emerged as a promising therapeutic agent due to its diverse pharmacological properties, including potent anti-inflammatory, neuroprotective, and immunomodulatory effects. CBD modulates immune responses, including the regulation of T cell activity, induction of macrophage apoptosis, suppression of pro-inflammatory cytokines, and modulation of signaling pathways involved in inflammation and immune homeostasis. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases to identify relevant preclinical and clinical studies on CBD’s immunomodulatory effects. Preclinical and clinical studies demonstrate its efficacy in treating autoimmune diseases such as Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, along with its potential in neuropathic pain and cancer therapy. Recent advancements in nanotechnology-based delivery systems have further enhanced CBD's therapeutic potential by improving its solubility, bioavailability, and targeted delivery, enabling innovative approaches for wound healing, inflammation management, and cancer treatment. However, challenges such as variability in immune responses, limited long-term safety data, and potential drug-drug interactions persist. This review comprehensively examines CBD’s pharmacokinetics, pharmacodynamics, and immunomodulatory mechanisms, highlighting its clinical potential, existing limitations, and future directions in advancing its integration into precision medicine and immune regulation.

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.

Immune checkpoint inhibitors (ICIs) have successfully transformed clinical oncology against various cancers. However, their widespread utility is limited by low response rates and severe adverse events; thus, a safe and effective approach is required to address these issues. Here, we report the nanoengineering of an anti-programmed cell death-1 antibody (aPD-1) to boost the therapeutic effects following direct local administration into tumors. Specifically, we prepared an aPD-1 nanoformulation using biocompatible mesoporous polydopamine nanoparticles (MPNs) that allow facile and efficient surface functionalization of aPD-1 via latent reactivity to proteins. The nanoformulation increased the antagonistic activity of aPD-1 against PD-1 receptors by enhancing their avidity interactions, effectively blocking PD-1 immune checkpoint signaling in T cells to restore their activation and effector function. The nanoformulation administered via local intratumoral injection enhanced tumor retention of aPD-1 and elicited strong antitumor efficacy against local tumors and long-term tumor recurrence. Our results indicate that robust immune checkpoint signaling blockade in the local tumors using nano-ICI treatment can effectively orchestrate antitumor immunity for local and systemic cancer treatment. Overall, this study underscores the potential of a biomaterial-based nanoengineering approach for improving the efficacy and safety of antibody-based ICI therapy with localized tumor treatment.

Cognitive impairment (CI) causes severe impairment of brain function and quality of life of patients, which brings a great burden to society. Cerebral hypoxia is an important factor in the pathogenesis of CI. Hyperbaric oxygen (HBO) therapy may mitigate hypoxia-induced CI, but its efficacy and mechanisms are not fully understood. In this study, a mice model of CI induced by hypoxia environment was established, then behavioral tests, pathological examination, metabolomic and lipidomic analyses, and molecular biology were used to assess the impact of HBO on hypoxia-induced CI. HBO was found to alleviate CI and pathological damage of hypoxia mice. Metabolomic, lipidomic, and molecular biology analyses showed that HBO increased the levels of oleic acid (OA) and membrane-bound O-acyltransferase 2 (MBOAT2), thereby altering the composition of membrane phospholipids (PLs) and reducing hypoxia-induced neuronal ferroptosis (FPT) to interfere with cognitive function in mice. In vitro experiments confirmed that OA and MBOAT2 led to membrane PL remodeling in a mutually dependent manner, affecting cell resistance to hypoxia-FPT. The results emphasized the combined effect value of OA and MBOAT2 in HBO for hypoxia-induced CI, and provided a novel perspective for the treatment of CI by HBO.

Therapeutic interventions can be designed by exploiting the immune system’s ability to initiate specific responses to various stimuli. However, specific T cell activation, which is a key target for vaccines and immunotherapies, remains challenging. Polysaccharides derived from microbial cell walls are promising immunomodulators that interact with pathogen-recognition receptors (PRRs) on dendritic cells and macrophages, triggering robust immune responses for modulating T cell function and activating effector or regulatory pathways. In this Review, we discuss the role of polysaccharides as pathogen-associated molecular patterns (PAMPs) recognized by PRRs and their immunomodulatory potential for biomedical applications. We examine the engineering aspects of polysaccharides, investigating their potential in vaccine, immunoadjuvant, immune-modulation and drug-delivery applications and highlighting their immune-activating or immune-regulatory functions. We also explore how trained immunity can be induced by polysaccharides to trigger immune responsiveness upon re-encountering pathogens. By leveraging materials engineering principles, polysaccharides can offer a platform for effective vaccines and immunotherapies against autoimmune and other diseases.

Cancer immunotherapy has revolutionized clinical cancer treatments by taking advantage of the immune system to selectively and effectively target and kill cancer cells. However, clinical cancer immunotherapy treatments often have limited efficacy and/or present severe adverse effects associated primarily with their systemic administration. Localized immunotherapy has emerged to overcome these limitations by directly targeting accessible tumors via local administration, reducing potential systemic drug distribution that hampers drug efficacy and safety. Sustained-release formulations can prolong drug activity at target sites, which maximizes the benefits of localized immunotherapy to increase the therapeutic window using smaller dosages than those used for systemic injection, avoiding complications of frequent dosing. The performance of sustained-release formulations for localized cancer immunotherapy has been validated preclinically using various implantable and injectable scaffold platforms. This review introduces the sustained-release formulations developed for localized cancer immunotherapy and highlights their biomaterial-based platforms for representative classes, including inorganic scaffolds, natural hydrogels, synthetic hydrogels, and microneedle patches. The design rationale and other considerations are summarized for further development of biomaterials for the construction of optimal sustained-release formulations.