BACKGROUND:Small cell lung cancer (SCLC) is highly malignant with limited treatment options. Chimeric antigen receptor macrophages (CAR-Ms) show potential for solid tumor therapy due to their phagocytic activity, tissue penetration, and immunomodulatory functions, but their application in SCLC remains unexplored. Delta-like ligand 3 (DLL3), a SCLC-specific membrane antigen, represents a promising therapeutic target. Here, we developed a DLL3-targeted CAR-M therapy and an enhanced strategy for SCLC immunotherapy. METHODS:DLL3-specific CAR-Ms were generated by introducing a CAR construct (DLL3-ScFv-CD8-CD3ζ) into murine and human macrophages via lentiviral transduction. A β-glucan (BG)-based training protocol was established to enhance CAR-M functionality. Phagocytic and cytotoxic activities were evaluated by flow cytometry and bioluminescence assays, and in vivo antitumor efficacy was assessed in immunodeficient and immunocompetent mouse models. RESULTS:Engineered CAR-Ms exhibited potent phagocytic and cytotoxic activity against DLL3-positive cells and effectively infiltrated and eliminated tumor spheroids in 3D culture systems. Intravenously administered CAR-Ms suppressed DLL3-positive lung cancer growth in both immunodeficient and immunocompetent models without discernible toxicity. Importantly, BG training enhanced CAR-M functionality by conferring sustained anti-tumor immunity, amplifying inflammatory and interferon pathway activation, and remodeling the tumor microenvironment through epigenetic and metabolic reprogramming. These findings establish BG-trained, DLL3-targeting CAR-Ms as a promising therapeutic approach for SCLC. CONCLUSION:Anti-DLL3 CAR-Ms demonstrate significant potential for solid tumor treatment and may offer a viable clinical strategy for SCLC in the future.

Despite emerging evidences showing the close link between immunosenescence and organismal aging, whether and how aged innate immune system drives systemic aging remains an enigma, and importantly, how primary senescence is initiated and regulated needs to be addressed. Herein we identified late endosomal/lysosomal adapter, MAPK and mTOR activator 5 (Lamtor5) as an age-dependent factor that controlled macrophage senescence and peripheral aging. Specifically, we demonstrated that Lamtor5 ablating macrophages displayed senescent signatures, metabolic defects, aging-related transcriptomic and epigenetic features, nicely concurring with macrophages from naturally aging mice. Importantly, delivery of senescent Lamtor5 ablating macrophages accelerated aging in young mice, while transplantation of young macrophages or senolytic elimination of senescent cells corrected the aging manifestation in myeloid Lamtor5 conditional knockout (CKO) mice. Mechanistically, Lamtor5 physically interacted with cGMP-AMP synthase (cGAS) and promoted its degradation in an ESCRT manner. Accordingly, application of macrophage-targeting cGAS small interfering RNA (siRNA) or a small peptide targeting the Lamtor5/cGAS interface profoundly alleviated aging-associated inflammation and tissue dysfunction in aged mice. Collectively, the findings shed the light on immunosenescence and its central role during organismal aging, thereby opening a new avenue for developing macrophage-based therapeutics to improve healthy aging.

ABSTRACT Tumor‐associated macrophages (TAMs) are central regulators of the tumor microenvironment (TME), with their metabolic states critically influencing tumor progression or regression. Although reprogramming TAM metabolism is a promising therapeutic avenue, clinical translation remains challenging due to the oversimplified understanding of macrophage plasticity. To bridge these gaps, we first provide an in‐depth analysis of the metabolic signatures and functional heterogeneity of TAMs, highlighting key pathways—glycolysis, fatty acid oxidation, and amino acid metabolism—that govern TAM functional diversity. Building on this foundation, we offer a comprehensive overview of current therapeutic strategies targeting critical metabolic regulatory nodes in TAMs and explore future directions for their clinical translation. Ultimately, we propose that precisely modulating the metabolic networks of TAMs can effectively reprogram their immunosuppressive functions, thereby opening new avenues for advancing cancer immunotherapy.

ABSTRACT Aging and age‐related diseases are a major public health concern, driving interest in anti‐aging research. While small molecules and natural compounds show promise in animals, clinical translation is limited. Recently, chimeric antigen receptor (CAR)‐engineered immune cells have achieved breakthroughs in treating non‐cancerous conditions like autoimmune diseases and organ fibrosis, highlighting their therapeutic potential. This review explains how the immune system counteracts aging through senescent cell clearance, reduction of pro‐inflammatory environments, and secretion of regenerative factors. It synthesizes principles of immune cell‐based anti‐aging therapies, analyzing preclinical and clinical studies. Key challenges include limited target specificity, immunosuppressive microenvironments, and variability in cell source and function. Future progress will require multidisciplinary collaboration—incorporating nanotechnology, synthetic biology, and targeted delivery—with artificial intelligence accelerating the development of personalized anti‐aging interventions. Cellular immunotherapies thus hold transformative potential for modulating aging and advancing precision medicine to extend global healthspan.

Maternal high-fat diet (HFD) can increase the risk of metabolic disturbances in offspring by modifying their gut microbiota, which may persist into adulthood. However, how HFD before pregnancy affects the carnitine mapping and alters the development of the gut microbiota in offspring remains to be explored. In this study, 4-week-old C57BL/6J mice were initially fed HFD for 10 weeks. The mice were subsequently mated and maintained on a normal diet during pregnancy. We investigated lipid metabolism, intestinal barrier function, and gut microbiota development in the offspring at various time points. We discovered that the carnitine development curve of the offspring in the HFD group was significantly different from that of the offspring in the control group. The expression of genes involved in lipid metabolism was altered significantly in the liver and colon. The development of the gut microbiota also significantly changed, and the degree of microbial invasion of the mucus increased. Specifically, the abundance of Akkermansia and Muribaculaceae increased significantly in the offspring, whereas the abundance of Bacteroides and Prevotellaceae UGG 001 decreased significantly in both the dams and offspring after maternal HFD before pregnancy. Maternal HFD before pregnancy, on the one hand, altered the developmental trajectory of the gut microbiota in offspring, impaired intestinal barrier function, and increased susceptibility to microbial infections. On the other hand, maternal HFD before pregnancy triggered an abnormal carnitine profile and disrupted lipid metabolism in the offspring.

Neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.

Skin aging is an inevitable biological process caused by cellular senescence and overexposure to harmful environmental factors such as ultraviolet (UV) radiation. Senescent fibroblasts with proliferation arrest, mitochondrial dysfunction and nicotinamide adenine dinucleotide phosphate (NADPH) depletion have been proposed as a major mechanism driving skin photoaging, but the specific therapies are currently lacking. Inspired by the self-powering potential of plant-derived photosynthetic system, we herein fabricated a novel nanophotosynthetic platform that integrated Chlorella-derived nanothylakoid units (NTUs) with hyaluronic acid (HA)-based microneedles (MNs) to specifically target senescent fibroblasts for treating skin photoaging. By equipped with photosynthesis (PS)-I/II and quinolinate phosphoribosyltransferase (QPRT), the NTU-MN photosystem remarkably increased mitochondrial biogenesis and adenosine triphosphate (ATP) generation, resumed NAD(P)H pool and increased cellular anabolism, addressing the heighted bioenergetic and biosynthetic requirement for highly turnover of fibroblasts during photoaging. Furthermore, with skin penetrating ability of MNs and camouflaging of fibroblast membranes, topical application of the nanophotosystem facilitated the intradermal release of NTUs, leading to regeneration of damaged tissues, increased collagen synthesis, decreased senescence-associated secretory phenotype (SASP), and hence alleviated photoaging of skin. Thus, we developed a “green nanoplatform” with significantly anti-aging efficacy, biocompatibility, and biosafety, opening new avenues for light-driven therapies for degenerative diseases.

Because of their distinct physical and chemical characteristics, soft materials with low modulus, great deformability, and large compliance have progressively emerged as a significant area of study. However, the responsiveness of traditional soft materials is inherently limited by passive diffusion and equilibrium thermodynamics. Thus, by incorporating stimuli-responsive artificial materials into motile bacterial species with anticancer properties, a soft biohybrid bacterial system has been created, converting soft materials from static scaffolding into adaptable, living systems. Specifically, the surface of Escherichia coli DH5α is modified by liposomes co-loaded with glucose oxidase and Tirapazamine (TPZ). The soft biohybrid bacterial system uses anaerobic targeting to deliver anticancer drugs and catalyzes glucose in the tumor microenvironment, consuming local oxygen in the process. The enhanced hypoxic microenvironment fully activates TPZ, significantly boosting its cytotoxic effect on tumor cells. Moreover, the soft biohybrid bacterial system further induces strong immunogenic cell death, which enhances the therapeutic effect while minimizing side effects on normal tissues. This innovative strategy offers a promising solution to overcome the therapeutic challenges associated with traditional soft materials.

Acute lung injury (ALI) is a clinically critical disease characterized by overwhelming inflammatory response and significant tissue damage with no specific treatment available currently. As a key player in the pathogenesis of ALI, macrophages are aberrantly activated and polarize toward the pro-inflammatory phenotypes, leading to overzealous inflammation and lung injury. Mitochondria is recognized as a crucial signaling hub governing macrophage function and polarization, deregulation of which is causatively related with defective metabolism of macrophages, deregulated inflammation, and hence ALI. Herein, an inflammation-responsive, biomimetic metal-organic framework (MOF) nanoplatform, termed a127/mito@ZIF@Ma is developed, which is sophistically designed for synergistic delivery of macrophage-derived mitochondria and anti-inflammatory miRNA-127 antagonist to resume pulmonary macrophages homeostasis and alleviate lung inflammation and injury. Notably, macrophage membrane encapsulation conferred the biomimetic MOF with enhanced transport efficacy both in vitro and in vivo. Therefore, the administration of the nanoparticles accordingly conferred a profound protection of mice against lung inflammation and injury induced by either bacterial or viral infection with unnoticeable tissue toxicity. The study thus devises a novel MOF-based nanosystem that integrates mitochondria transplantation and miRNA therapeutics, which may open a new avenue for treating ALI and relevant critical diseases.

Methicillin-resistant Staphylococcus aureus (MRSA) is a highly virulent and drug-resistant pathogen frequently causing bacterial pneumonia. Currently, there are limited effective treatments available due to the rapidly evolving resistance of bacteria. Therefore, there is an urgent need to develop novel therapies that focus on host-pathogen interactions. Oridonin is a naturally occurring diterpenoid with multiple pharmacological effects, but its therapeutic potential in bacterial pneumonia, as well as its action mode, remains largely unknown. Here, we demonstrated that oridonin conferred protection against MRSA pneumonia. Macrophages, the major innate immune cells against respiratory infection, exhibited enhanced bactericidal capability, alleviated inflammatory response, and resistance to ferroptosis upon oridonin treatment. Importantly, we further showed that oridonin covalently associates with the Kelch-like ECH-associated protein 1 (KEAP1), hindering its binding by nuclear factor erythroid 2-related factor 2 (NRF2). Enhanced activation of NRF2 subsequently activated the genes responsible for mitochondrial lipid peroxidation and iron homeostasis, thereby orchestrating the activity and survival of alveolar macrophages. Collectively, we present the first evidence demonstrating the therapeutic potential of oridonin in combating drug-resistant bacterial pneumonia, establishing it as a novel regulator of both mitochondrial and ferroptotic pathways. This may have significant implications for the development of host-directed therapies against formidable pathogens.

Methicillin-resistant Staphylococcus aureus (MRSA) represents a predominant multidrug-resistant pathogen that may cause severe bacterial pneumonia. Alveolar macrophages (AMs) serve as the first defensive line against respiratory infections to maintain tissue homeostasis. Licochalcone D (Lico D), a bioactive flavonoid from Glycyrrhiza uralensis, demonstrates protective efficacy against various pulmonary disorders. However, the potential of Lico D to modulate innate immune responses of AMs against bacterial pneumonia and the underlying mechanisms remain unexplored. We herein demonstrate that Lico D remarkably alleviates MRSA-induced pneumonia and protects AMs from ferroptosis. This protective effect is mediated through the suppression of mitochondrial oxidative stress and, more importantly, modulation of lipid metabolism. Specifically, our data elucidate that Lico D directly targets the vacuolar protein sorting 4 homolog A (VPS4A), a newly identified sensor for lipid droplets (LDs), and disrupts its interaction with LC3 for lipophagy to generate free fatty acids (FFAs). Accordingly, Lico D treatment lessens lipid peroxidation (LPO) and hence ferroptosis of macrophages, leading to efficient antibacterial response and inflammation resolution. Collectively, we uncover the VPS4A-targeting and AMs-protecting effects of Lico D, providing new insights into the pathogenesis of MRSA pneumonia and the treatment of critical biotic-resistant pathogens.

ABSTRACT Climate change presents significant challenges to plant growth and reproduction. Clonal plants, with low genetic diversity, are particularly vulnerable due to their limited adaptive capacity. Plant-associated microbiomes can play a crucial role in enhancing clonal plant survival and adaptability, yet the mechanisms governing microbial community assembly along the soil-episphere-endosphere continuum remain unclear. In this study, we investigated microbial community assembly patterns in the clonal plant Glechoma longituba . Our findings demonstrate that the assembly of microbial communities is primarily driven by host-related factors rather than external environmental filtering. First, host selection reduced α-diversity and network complexity while increasing β-diversity and community stability. Second, the mechanisms of microbial assembly transitioned from stochastic dominance in bulk soil and epiphytic compartments to deterministic processes within endophytic niches. Third, the taxonomic structure exhibited significant turnover along the soil-episphere-endosphere continuum, accompanied by functional redundancy to maintain ecosystem functions. The results support the hypothesis that host selection optimizes the functional composition of microbial communities by reducing diversity and network complexity while ensuring the stability of key functional microorganisms. The study emphasizes the critical role of host-microbe interactions in sustaining the adaptive and functional advantages of clonal plants, offering insights into managing sustainable plant communities under climate change. IMPORTANCE This study highlights the vital role of plant-associated microbiomes in helping clonal plants, which have low genetic diversity, adapt to climate change. By examining the clonal plant Glechoma longituba , the research reveals that the plant itself plays a key role in shaping its microbial communities, rather than external environmental factors. Host selection simplifies microbial diversity and network complexity but enhances community stability and functional efficiency. These findings suggest that clonal plants can optimize their microbiomes to maintain critical functions. This work provides valuable insights into how plants and microbes interact to improve resilience, offering potential strategies for managing plant communities in a changing climate. By understanding these mechanisms, we can better support sustainable ecosystems and agricultural practices in the face of global environmental challenges.

High-fat diet (HFD) has been demonstrated to negatively affect the exacerbation of chronic diseases, such as obesity, diabetes, gastrointestinal disease, cardiovascular disease, and central nervous system disease. Research has revealed that maternal HFD affects the intestinal barrier integrity of offspring in multiple ways. Offspring not only "inherit" the abnormal gut microbiota induced by maternal HFD, thus having long-term effects on offspring health, but also are profoundly affected by various factors, such as the placental environment, mode of birth, and breast milk nutrition. In this review, we summarize recent epidemiological studies, clinical studies and animal experiments, and we evaluate the threat of maternal HFD to offspring health. We discuss the associations between maternal HFD and the intestinal barrier of offspring in the context of maternal-infant influence pathways, the gut microbiota and associated metabolism, intestinal physical barriers, and intestinal immune barriers. Further, we interpret the available evidence and its limitations. We believe that medical professionals and society must respond to the harmful effects of HFD to improve outcomes in the future.

Although evidence indicates that the incidence of viral pneumonia is causally associated with disturbances in the microbiome and hypoxic status in the gut, there is currently no effective strategy for the co-delivery of probiotics and oxygen through oral administration. We therefore created a spatiotemporal biosystem by preparing Bacillus coagulans (BC) probiotic spores, coating them with a polydopamine/chitosan (PCS) nanocoating, and conjugating them with CaO2 nanoparticles. CaO2@PCS@BC spore rapidly diffused across the mucus layer spatially while released oxygen followed by bacterial proliferation temporally, thereby significantly enhancing the oxygen levels within intestinal epithelial cells by effectively overcoming the barriers posed by mucus layer and oxygen gradient. In a mouse model of H1N1 infection, we demonstrated that oral CaO2@PCS@BC spore treatment reversed gut dysbiosis, alleviated intestinal hypoxia, improved metabolism, restored immune balance, and mitigated symptoms of viral pneumonia. Finally, CaO2@PCS@BC spore facilitated spatial recovery and preserved the anaerobic environment of the gut lumen, suggesting significant biosafety. In conlusion, we have developed a spatiotemporal biosystem that effectively co-delivers probiotics and oxygen to mitigate intestinal dysbiosis in the treatment of viral pneumonia through the gut-lung axis.

Lung disease remains a persistent global health challenge. Advances in medical research have led to innovative strategies to combat these conditions, with biomaterials emerging as a promising platform for targeted drug delivery. Various biomaterials-including nanoparticles such as liposomes, polymers, hybrid systems, dendritic polymers, gold nanoparticles, mesoporous silica, calcium carbonate, and exosomes-exhibit excellent biocompatibility. These materials protect therapeutic agents from nuclease degradation, stabilize drug carriers, and enhance cellular uptake via mechanisms such as endocytosis. Chemical modifications further improve biomaterials by facilitating endosomal escape and conjugation with targeting ligands, thereby enabling precise delivery to specific cells or tissues. As a therapeutic modality, mRNA offers high biosafety, notable controllability, efficient translation, and immunomodulatory properties. This review evaluates the impact of lung structure on drug absorption, examines delivery mechanisms associated with various biomaterial types, and presents application examples. It also summarizes recent research developments, discusses clinical limitations, and explores future research directions for biomaterials in lung disease therapy. Additionally, it highlights the role of biomaterials in stabilizing and protecting mRNA, providing insights into the advancement of mRNA-based therapeutics. This review aims to establish a robust theoretical foundation and offer practical guidance for biomaterial-based mRNA therapies in treating lung diseases.

Living treatments signify novel anticancer strategies employing living microorganisms with selective tropism to achieve effective therapeutic results. Nevertheless, the effective translation of bacterial biological products into clinical applications is still challenging, mainly because primitive microorganisms demonstrate limited therapeutic potential in tumor treatment. The hybridization of living bacteria with synthetic ingredients can provide diverse therapeutic functions to the targeted area, facilitating various interactions that offer exceptional therapeutic prospects compared to those of unhybridized living microbes. Here, αPD1 antibody-engineered Lactobacillus rhamnosus GG (LGG) is hybridized with sonopiezocatalytic BaTiO3 nanoparticles (BTO NPs) for enhanced tumor-targeted accumulation and antitumor therapy. Targeted delivery of the system to tumor hypoxic regions utilizes the hypoxia affinity of LGG. Ultrasound irradiation of BTO NPs generates reactive oxygen species through a piezoelectric catalytic reaction, which induces immunogenic cell death (ICD) of tumor cells. The accompanied oxygen production during the piezoelectric catalysis mitigates tumor hypoxia, working in conjunction with probiotics to enhance significant and sustained antitumor immune activation, thereby augmenting the efficacy of immune checkpoint blockade (ICB) therapy. This study proposes an engineered and hybridized microbial-based tumor immunotherapy approach for selective and ultrasound-controllable tumor catalytic therapy.

Cellular senescence is a significant risk factor for aging and age-related diseases (ARD). The canonical senolytics Dasatinib and Quercetin (DQ) have shown promise in clearing senescent cells (SnCs); however, the lack of selectivity poses a challenge in achieving optimal outcomes. Despite the recent occurrence of nanomaterial-based approaches targeting SnCs, limited therapeutic effects, and potential toxicity still remain a major concern. Herein, a "double locks-like" nanoplatform is developed that integrated Galactan coating and mesoporous polydopamine to encase the senolytic drug DQ. By this way, DQ is only released in SnCs that are featured with higher levels of β-galactosidase (β-gal) and low PH. Additionally, the nanoparticles are equipped with 2,2,6,6-Tetramethylpiperidine-1-oxyl (Tempo) to gain enhanced photothermal converting potential. Consequently, the synthesized nanosenolytics demonstrate remarkable specificity and efficacy in eradicating SnCs, and accordingly reverse pulmonary fibrosis in mice without affecting normal tissues. Upon exposure of near-infrared (NIR) light, the nanoparticles demonstrate to efficiently remove senescent tumor cells inducted by chemotherapy, thereby hindering the outgrowth and metastasis or breast cancer. Collectively, the present study develops an "On/Off" switchable nanoplatform in response to SnCs, and produces a more safe, efficient, and feasible way to delay aging or alleviate age-associated diseases.

Citation: Pavan A, Shi L and Abbas M (2024) Editorial: Updates on combination therapy for lung cancer volume II. Front. Oncol. 14:1393278. doi: 10.3389/fonc.2024.1393278