Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe2+ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H2O2 and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe2+ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe2+-binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan.
Platinum-based chemotherapy is widely used in cancer care but carries a substantial risk of cochleotoxicity and vestibulotoxicity. This study aimed to characterize early (3-month) and long-term (1-year) auditory and vestibular effects of platinum derivatives in adults, with the goal of improving monitoring strategies. A total of 110 adults (34-81 years; 63 female) received cisplatin (n = 73), carboplatin (n = 22), or sequential cisplatin followed by carboplatin (ciscarbo; n = 15). Assessments at baseline, 3 months, and 1 year included conventional and extended high-frequency (EHF) audiometry, distortion product otoacoustic emissions (DPOAEs), speech perception, auditory brainstem response (ABR), and envelope following response (EFR). Vestibular testing comprised vHIT and cVEMP. Ototoxicity was classified using ASHA (1994) and graded with TUNE. Linear mixed models assessed treatment- and time-related changes. Cisplatin induced significant threshold shifts across the audiogram, including low, mid, high, and extended high frequencies, with progression up to 1 year. Low- and mid-frequency thresholds remained largely stable in the carboplatin group, while the ciscarbo group showed early mid- and EHF deterioration. EHF thresholds increased across all groups. ASHA-defined ototoxicity was present in 73.5% at 3 months and > 90% at 1 year. DPOAEs revealed early, progressive OHC dysfunction, and ABR and EFR indicated neural involvement, particularly after cisplatin. Speech perception remained stable, and no significant vestibular deficits were detected. Cisplatin induces broad, progressive cochleotoxicity, while carboplatin produces milder, delayed effects. EHF audiometry, DPOAEs, and electrophysiological measures enhance early detection. Combining behavioral and objective markers with standardized grading supports comprehensive ototoxicity monitoring.
Link prediction is important across biological, social, and technological networks, but many methods either require domain-specific node attributes, do not scale to large graphs, or miss higher-order topology. We present BLANT-Predict, a topology-only framework that uses sampled graphlets and orbit-pair frequencies to rank likely missing edges. Across 12 real-world networks (up to about 1 million nodes and 3 million edges), we compare against 13 baseline methods and observe higher precision with strong scalability. Beyond standard k-fold cross-validation, we evaluate predictions against future out-of-sample network snapshots to better reflect real deployment. BLANT-Predict maintains superior precision in these future tests, indicating practical value for predicting previously unobserved links.
The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, Nε-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible. Here, we report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. We demonstrate that CMLase effectively reverses CML modifications in model proteins in vitro and in human tissue samples from elderly donors, providing proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. Collectively, our approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease.
Medical oxygen delivery systems require adaptable connection interfaces capable of supporting different clinical configurations during oxygen therapy. Integrating multifunctional connection mechanisms within a single component offers an opportunity to improve system versatility and connection management in respiratory care settings. To design and experimentally validate a novel dual-connection fitting for medical oxygen delivery, designated as the O2 Mixed Fitting, that enables simultaneous attachment of both a bubble humidifier and conventional oxygen tubing while remaining installed on the flowmeter. A comprehensive state-of-the-art review informed the conceptual development of the device. Iterative design refinement was performed using computer-aided design. The final device was manufactured by injection molding using medical-grade Acrylonitrile Butadiene Styrene. Validation included gas flow analysis, leak and pressure-holding tests, microbiological and physical stability evaluation under controlled climatic conditions, and sustainability assessment using a structured eco-design framework. The integrated dual-connection mechanism enabled transition between humidified and non-humidified oxygen delivery without detachment from the flowmeter. Gas flow measurements remained within predefined accuracy tolerances, including ±0.5 L/min at low flows and ±10% at higher flows. No leakage was detected during pressure testing up to 10 psi. During the 12-month natural stability study, physical and microbiological parameters remained within predefined acceptance criteria under climatic zone IVb conditions. The eco-design assessment demonstrated favorable environmental performance. The O2 Mixed Fitting represents an innovative dual-connection solution for medical oxygen delivery applications. Laboratory validation confirmed structural integrity, flow stability, pressure resistance, and physical and microbiological stability under the evaluated conditions. The integrated design enhances functional versatility while maintaining full compatibility with existing clinical infrastructure. Further clinical and operational studies are warranted to evaluate its potential impact on patient care and clinical workflow.
Isothermal nucleic acid amplification offers advantages over qPCR for decentralized diagnostics but remains constrained by rigid primer design, detection complexity, and equipment dependence. Recombinase-based systems operate at lower temperatures than other isothermal methods but require long primers and auxiliary enzymatic processing for detection. Here we introduce Annexing Isothermal Nucleotide Amplification (ANINA), a probe-guided recombinase-based framework integrating amplification and detection at ambient temperatures within a single lyophilized reaction. An Annexing Probe recruits short primers through spatial annexation, enabling efficient amplification at 25 °C within 30 minutes and direct lateral flow detection without auxiliary enzymatic processing. We show this framework detects attomolar WSSV and EBV DNA in abundant host gDNA, supports target-specific detection of DNA and RNA viruses and bacteria in contrived matrices, enables quantitative real-time detection comparable to qPCR, and facilitates a fully equipment-free 45-minute sample-to-answer workflow that detects early viral infection in a natural host model with qPCR-level sensitivity and improved performance over a commercial antigen test.
Aortic valve stenosis (AVS) is a sexually dimorphic cardiovascular disease characterized by fibro-calcification of the aortic valve leaflet. Sex differences in AVS arise in part from sexually dimorphic serum composition that differentially regulates valvular interstitial cell (VIC) myofibroblast activation. However, how individual serum factors contribute to sex-specific drug responses remains unknown. Here, we integrate serum proteomic profiling with in vitro drug screening using hydrogel biomaterials to identify sex-specific regulators of antifibrotic drug efficacy. We found that serum insulin-like growth factor binding protein 2 (IGFBP2) mediates Evogliptin resistance in female VICs cultured with female AVS serum through the activation of Rho/ROCK and focal adhesion kinase signaling. Our findings highlight IGFBP2 as a candidate biomarker for stratifying female patients with AVS for Evogliptin treatment, underscoring the need to incorporate sex as a biological variable in determining AVS treatments.
Cancer cells counteract oxidative stress through upregulation of antioxidant networks. Peroxiredoxin 3 (PRX3), a mitochondrial antioxidant enzyme, regulates reactive oxygen species homeostasis and promotes tumor cell survival. The natural compound thiostrepton (TS) covalently inhibits PRX3, disrupting redox balance and selectively induces tumor cell death. Mesothelioma, an aggressive malignancy, has limited therapeutic options, particularly in relapsed or refractory settings. Here, we demonstrate genetic deletion of PRX3 impairs mitochondrial bioenergetics and suppresses mesothelioma growth, while pharmacological inhibition of PRX3 with TS induces apoptosis in patient-derived mesothelioma explants. In a phase 1 trial treating patients with relapsed pleural mesothelioma and malignant pleural effusion (NCT05278975), weekly local intrapleural treatment with the TS formulated drug product RSO-021 at 90 mg is well tolerated leading to disease control in 67% of patients at 12 weeks and is associated with tumor reductions. Primary endpoints of safety, tolerability and dose finding were met, and secondary endpoints of pharmacokinetics, objective response rate, disease control rate, and progression free survival are explored. Genomic screening identified Solute Carrier Family 7 member 11 (SLC7A11) as a mediator of TS resistance, suggesting combined targeting may further enhance the pro-oxidant activity of RSO-021.
BCMA-directed CAR-T cell therapy has demonstrated remarkable clinical efficacy in multiple myeloma, but robust methods to evaluate product quality and predict long-term functionality remain underdeveloped. While immunophenotypic features of leukapheresis products correlate with clinical outcomes, the characterization of infused CAR-T cell products remains challenging and inconsistent across studies. We compared two versions of our academic BCMA-CAR product, CARTemis-1, differing only in their costimulatory domains (4-1BB vs. CD28), and performed a detailed functional and molecular characterization before and after antigen stimulation to identify which analytical approaches best capture functionally relevant differences between CAR-T cell products. Analyses included conventional flow cytometry, short-term cytotoxicity assays, repetitive antigen stimulation, metabolic profiling, and transcriptomic evaluation. Finally, metabolic profile of patient derived CAR-T cells products (n = 15) was also analyzed. Although previous studies have reported functional differences between CAR-T cell products incorporating distinct costimulatory domains, conventional assays in our system revealed no significant differences in viability, expansion dynamics, immunophenotype, or activation/exhaustion marker expression. In contrast, more functionally demanding assays revealed clear differences between constructs. Repetitive antigen stimulation revealed superior long-term cytotoxicity in CARTemis-1-BB, while metabolic profiling demonstrated enhanced spare respiratory capacity and maximal respiration after antigen exposure. Transcriptomic analysis further showed distinct pathway regulation, with enrichment of T cell activation signatures in CARTemis-1-BB and Wnt/TGFβ-related responses in CARTemis-1-28. Importantly, metabolic profiling of infused CAR-T cell products also identified distinct signatures associated with clinical outcome, distinguishing products administered to long-term responders from those infused into short-term or non-responding patients. Persistence and metabolic analyses represent key tools for optimizing CAR-T cell construct selection during preclinical development, providing a more accurate assessment of CAR-T cell product quality than standard immunophenotyping and enabling the identification of constructs with superior therapeutic potential.
Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.
Elongases are essential enzymes in the biosynthesis of sex pheromones in many lepidopteran species, where together with desaturases they determine pheromone precursor carbon skeletons and contribute to species-specific chemical communication. Despite their presumed importance, no fatty acyl elongase involved in lepidopteran sex pheromone biosynthesis has been functionally characterized to date. The rice leaffolder, Cnaphalocrocis medinalis, utilizes a blend of C18 monounsaturated aldehydes and alcohols as its sex pheromone, implying a critical elongation step from C16 precursors. Here, transcriptome analysis of the pheromone gland identified 45 candidate genes potentially involved in pheromone biosynthesis. Functional assays in Nicotiana benthamiana established a desaturation-elongation pathway in which the Δ11 desaturase Cmed070400 produces (Z)-11-hexadecenoic acid, which serves as the substrate for elongation. Multiple elongases, including Cmed092440, Cmed063180 and Cmed153360 catalyzed the conversion to (Z)-13-octadecenoic acid, the direct precursor of the major pheromone component. These findings provide the first experimental evidence for elongase-mediated formation of C18 pheromone precursors in C. medinalis. The identification of a minimal set of functionally active enzymes enables reconstruction of this pathway in plant systems, offering a basis for sustainable production of pheromone precursors for pest management applications.
Compared with chimeric antigen receptor (CAR) T cell therapy, antibody-drug conjugates (ADCs) offer distinct advantages. Here, we report on two FGFR4-targeted ADCs, using the high-affinity monoclonal antibody 3A11, the same binder used in a CAR T cell format that is being evaluated at the NCI (NCT06865664) for patients with relapsed/refractory rhabdomyosarcoma (RMS). These ADCs, conjugated to monomethyl auristatin E (MMAE) or an exatecan derivative, are rapidly internalized, causing potent fibroblast growth factor receptor 4 (FGFR4)-dependent cytotoxicity in vitro. In subcutaneous RMS xenograft models, both ADCs demonstrated robust anti-tumor activities, significantly prolonging survival. Notably, exatecan-ADC showed better efficacy, with durable tumor control, in aggressive fusion-negative (FN) RMS559 and fusion-positive (FP) RH4 RMS cell-line-derived xenografts (CDXs) and a patient-derived RMS xenograft (PDX). Furthermore, exatecan-ADC effectively controls tumors in an FGFR4-expressing MDA-MB-453 breast cancer mouse model, eradicating relapsed tumors with retreatment. These findings highlight FGFR4-targeted ADCs as potent therapeutic agents against aggressive FGFR4-expressing malignancies, supporting their further clinical development.
Colony-stimulating factor-1 receptor (CSF-1R) is a class III receptor tyrosine kinase that regulates monocyte/macrophage lineage cells, including microglia, and has emerged as an attractive target for neuroinflammation-associated neurodegenerative diseases. Inspired by the clinical relevance of dual CSF-1R/c-Kit inhibition and building upon our previously reported 5-methylisoxazole-based lead scaffold, we designed and synthesized a new series of 2-amino-oxazole-based inhibitors by replacing the original 5-methylisoxazole hinge-binding motif with a 2-amino-oxazole core, thereby introducing an additional hydrogen-bond donor. Structure-activity relationship studies revealed that CSF-1R/c-Kit inhibitory activity was strongly influenced by N-substitution, amide bond directionality, and the spatial arrangement of basic amine-containing R groups. Notably, modification of the terminal aryl substitution pattern from 1,3,5 to 1,3,4 enabled improved positioning of pendant amines and afforded several low-nanomolar CSF-1R/c-Kit inhibitors. Integrated biochemical, cellular, kinome, and in vitro ADME profiling identified 12l and 11o as the most promising lead candidates. In SIM-A9 microglial cells, both compounds suppressed CSF-1-induced ERK phosphorylation, a downstream readout of CSF-1R signaling. Compound 12l showed potent dual CSF-1R/c-Kit inhibition, suppression of CSF-1-induced ERK phosphorylation, favorable microsomal and plasma stability, high BBB-PAMPA permeability, and a cleaner kinome selectivity profile. Compound 11o exhibited particularly strong c-Kit inhibition, suppression of CSF-1-induced ERK phosphorylation in SIM-A9 cells, and favorable ADME properties. These findings identify 12l and 11o as promising dual CSF-1R/c-Kit inhibitor leads for further development toward neuroinflammation-associated neurodegenerative diseases.
Diabetes encompasses a range of diseases characterized by chronic hyperglycemia and serious health complications. However, predicting therapeutic response in latent autoimmune diabetes in adults (LADA) remains a major challenge, limiting the development of personalized treatment strategies. LADA is a relatively newly defined diabetes type that shares features of Type 1 diabetes (T1D) and Type 2 diabetes and is estimated to be more prevalent than T1D. We developed a LADA model in NOD mice and assessed combination treatment (CT) comprising GABA, sitagliptin, and omeprazole. Surprisingly, ∼30% of the CT-treated mice completely recovered, exhibiting normoglycemia and insulin independence. We identified two cell-free RNA markers, Adgrb1 and Chd5, that distinguish responders from nonresponders, indicating promising predictive ability. These discoveries offer a potential diagnostic tool for identifying LADA patients who could benefit from CT, representing an advance in personalized diabetes treatment. CT-induced β-cell neogenesis involved replication, providing valuable insights into β-cell regeneration mechanisms. Furthermore, the cured mice exhibited insulitis primarily populated by T regulatory Type 1 cells, potentially suppressing autoimmunity and facilitating β-cell survival and regeneration. This study opens new avenues for targeted LADA therapies and paves the way for precision medicine in diabetes management.
Stroke remains a leading cause of mortality worldwide, demanding rapid, accurate diagnosis; distinguishing stroke types matters because treatments differ significantly. Using a recently developed, non-invasive brain scanner integrating a 16-antenna radio-frequency array, we present a deep-learning model that distinguishes the two main stroke types. We employ masked autoencoder-based self-supervised learning and supervised contrastive strategies to improve data efficiency and robustness with limited labeled clinical data. In the current test cohort, the system achieved 92% sensitivity and 85% specificity for hemorrhagic versus non-hemorrhagic detection, and 95% sensitivity and 80% specificity for ischemic versus non-ischemic cases. Beyond classification, the model showed patterns consistent with an ordering of relative dielectric permittivity across conditions (hemorrhagic, ischemic, mimic, and healthy). While not representing direct measurement of tissue dielectric properties, these observations provide insight into relative dielectric differences captured by the RF measurements. These findings support the potential of RF-based measurement-domain analysis to more reliable differentiation between stroke subtypes.
Although the hemagglutination inhibition (HAI) titer remains the gold standard correlate of protection against influenza, it does not fully capture the broader antibody responses that contribute to immunity. We analyzed immune responses in paired pre-infection and convalescent sera from 306 RT-PCR-confirmed A(H3N2) infections from two household studies (2014-2018) in Managua, Nicaragua. Antibody responses were measured by HAI and enzyme-linked immunosorbent assays (ELISAs) against full-length hemagglutinin (HA), the HA stalk, and neuraminidase (NA). Participants were classified as HAI responders (≥ 4-fold HAI rise), alternate responders (no HAI rise but ≥ 4-fold boost in ≥ 1 ELISA), or no-response individuals (no ≥ 4-fold rise in any assay). We compared demographic, clinical, and pre-infection antibody characteristics across these groups. We also analyzed predictors of an NA response. Overall, 77% of participants had HAI seroconversion or a fourfold rise. Among the 23% HAI non-responders, 62% had alternate antibody responses. No-response individuals had the highest pre-infection HAI and full-length HA titers (p < 0.01), the lowest viral loads, and the lowest frequency of fever or influenza-like illness symptoms (p < 0.01). An NA response was more common among symptomatic individuals and moderate baseline titers, with both low and high extremes reducing NA response odds. High baseline HAI titers can limit detectable fourfold rises and are associated with milder illness. Evaluating additional immune responses may capture a more complete picture of the host response to infection, thereby improving surveillance and informing vaccine development.
Circulating tumor cells (CTCs) and platelets might be collected simultaneously during liquid biopsy; however, their interaction in the form of platelet-covered CTCs (pcCTCs) remains only partially understood. In this study, we aimed to detect and characterize pcCTCs using single-cell data from peripheral blood mononuclear cells (PBMCs) and to compare their transcriptomic profiles with naked CTCs and platelets. We analyzed 22 samples (10 from breast cancer patients and 12 from ovarian cancer patients) and 7 controls (3 non-malignant samples and 4 healthy donors) to identify candidate CTCs and pcCTCs. We identified 12 candidate CTCs: 5 naked CTCs and 7 pcCTCs in 5 patients in total. We next examined genes associated with epithelial-mesenchymal transition (EMT), angiogenesis, extracellular matrix organization, and platelet activation, signaling, and aggregation. These pathways were found to be upregulated in pcCTCs exhibiting the highest platelet-associated signal. We computed scores for epithelial and mesenchymal CTC phenotypes, platelet-related signatures, and gene sets associated with ovarian and breast cancer CTCs. Transcriptomic analysis revealed that platelet cloaking significantly influences genes connected with CTCs survival in the bloodstream and metastatic progression.
Spike trains from spinal motor neurons contain low-frequency components that modulate muscle force, and higher-frequency components (above 10 Hz) that do not. The functional role of these higher-frequency components in motor control is still debated. We investigated whether mental tasks that modulate the power of cortical oscillations produce corresponding modulations in spinal motor neuron activity above 10 Hz without affecting force output. Such coupling would indicate that some higher-frequency components are not merely arising as a byproduct of force generation nor indirectly contributing to motor control, but simply reflect cortical oscillations propagating to spinal motor neurons. If voluntary power modulations of these higher-frequency oscillations do not affect force output, they could potentially serve as control signals for neural interface applications such as movement augmentation or motor neuroprostheses. We recruited 15 human participants and recorded high-density electromyography signals (HD-EMG) from the tibialis anterior muscle, as well as electroencephalography (EEG) signals. The cumulative spike train (CST) was computed from the activity of spinal motor neurons decoded from HD-EMG signals. The participants performed sustained dorsiflexion concurrent with foot motor imagery, hand motor imagery, mental arithmetic, or no specific mental task. We analysed the bandpower correlation between EEG and CST signals as well as evaluated the task discriminability of CST bandpower signals with a linear classifier. At the intra-muscular coherence peak, we found statistically significant power correlations between CST and EEG in two separate analyses: first, when correlating across individual trials regardless of the mental task, and second, when correlating across the four mental tasks (Kendall's τ coefficient [Formula: see text], [Formula: see text] respectively; mean ± std. dev.). To evaluate the potential of the CST as a control signal, we classified the mental tasks based on CST bandpower and obtained classification accuracies slightly but significantly above chance level ([Formula: see text]; chance level = 25%). These results show that mental tasks can simultaneously modulate the power of cortical and spinal oscillations. This supports the notion that cortical oscillations not contributing to ongoing force control can propagate to the spinal level. We further demonstrate that mental tasks can be classified from CST bandpower, but classification performance is limited by the low signal-to-noise ratio.
The endometrial immune environment regulates maternal immune tolerance and plays a key role in embryo implantation. We investigated whether its impact on reproductive outcomes differs between fresh and frozen embryo transfer (FET) cycles. In this prespecified secondary analysis of a prospective randomized study, 493 good-prognosis IVF patients underwent endometrial immune profiling before embryo transfer. Patients with a balanced profile received standard care, whereas those with immune dysregulation were randomized to conventional or immune-guided precision care. Live birth rates (LBRs) were analyzed according to immune status, transfer type, and treatment strategy. A transfer type-specific effect was observed. In FET cycles, a balanced immune profile was associated with higher LBR compared with immune dysregulation (52.4% vs. 14.7%; adjusted OR 5.32 [95% CI 1.53-20.92]; ARD +37.7%). Precision care improved LBR compared with conventional management (48.6% vs. 14.7%; OR 5.03 [1.66-17.63]; ARD +33.9%). No significant association between immune status and reproductive outcomes was observed in fresh transfers. The impact of the uterine immune environment differed according to embryo transfer type and was predominantly observed in FET cycles. These findings suggest that endometrial immune competence may be particularly relevant to implantation success after frozen embryo transfer and warrants confirmation in larger prospective studies.
The complement system is essential for distinguishing self-tissue from foreign threats; however, complement activation on biomedical surfaces such as implants, transplants, or drug-delivery systems may lead to severe thromboinflammatory complications. Unlike systemic complement inhibitors, surface-targeted strategies remain scarce, despite their potential advantages regarding safety and efficacy. Recent years have seen the emergence of diverse surface-targeting approaches that impair different mechanisms underlying complement-mediated complications. These strategies, ranging from surface coatings to inhibitors targeting complement-tagged surfaces, are progressing from conceptual development to clinical application. In this review, we provide a comprehensive overview of complement-activation mechanisms on biomedical surfaces, highlight ongoing clinical investigations, and discuss a broad spectrum of emerging approaches to prevent adverse complement activation on biomedical interfaces.