Innate Mechanisms Research Articles

A Guide to Chemical Considerations for the Pre-Clinical Development of Oligonucleotides.

Oligonucleotide therapeutics, a pioneering category of modern medicinal drugs, are at the forefront of utilizing innate mechanisms to modulate gene expression. With 18 oligonucleotide-based FDA-approved medicines currently available for treating various clinical conditions, this field showcases an innovative potential yet to be fully explored. Factors such as purity, formulation, and endotoxin levels profoundly influence the efficacy and safety of these therapeutics. Therefore, a thorough understanding of the chemical factors essential for producing high-quality oligonucleotides for preclinical studies is crucial in their development for further clinical application. This paper serves as a concise guide to these chemical considerations, aiming to inspire and equip researchers with the necessary knowledge to advance in this exciting and innovative field.

Assessing molecular genetic and immunological predictors of COVID-19 course in healthcare worker risk group

Relevance. Studying features of innate and adaptive mechanisms of immune response in medical workers (MW), the most vulnerable social group with a high risk of infection, is an urgent research task. The aim of the study: Comprehensive study of innate and adaptive immune mechanisms and analyzing relationships between clinically significant polymorphisms (SNPs) in TLR2, TLR4 genes, TLR2 expression level on peripheral blood monocytes, peripheral blood cytokine profile (IL-1β, IL-10, IL-6, IFNγ, platelet activation marker) and SARS-CoV-2-specific humoral immune response in medical workers (MW) at a temporary infectious disease hospital in early and late COVID-19 convalescence. Materials and methods. immunologic, cytofluorimetric and molecular-genetic research methods were applied. Adaptive immune response in medical workers — COVID-19 convalescent subjects. Results. Early post-COVID-19 convalescence period in MW was linked to higher TLR2 monocyte expression; the mean fluorescence intensity was significantly elevated by 1.5-fold compared to control group. Late convalescence period (7 months post-COVID-19) was characterized by lowered serum IFNγ level. A decline in IFNγ production was significant: decreased by 82-fold in MR that was markedly stronger compared to control group (59 times). The imbalance of cytokines controlling antiviral innate and adaptive immune response was revealed in MW with identified combination of polymorphisms rs5743708 and rs4986790 in TLR2, TLR4 genes with the rate not exceeding 6.7%. It was found that 7 months after COVID-19 there was a markedly decreased IFNγ, IL-1β and IL-10 levels. The studies indicate both altered innate and adaptive immune mechanisms and a need to optimize therapeutic and prophylactic measures aimed at increasing patient-intrinsic resistance, protection of respiratory tract mucosal barriers and identification of genetic predictors of defects in innate and adaptive immune response in medical workers — COVID-19 convalescent subjects.

Targeted degradation of membrane and extracellular proteins with LYTACs.

Targeted protein degradation technology has gained substantial momentum over the past two decades as a revolutionary strategy for eliminating pathogenic proteins that are otherwise refractory to treatment. Among the various approaches developed to harness the body's innate protein homeostasis mechanisms for this purpose, lysosome targeting chimeras (LYTACs) that exploit the lysosomal degradation pathway by coupling the target proteins with lysosome-trafficking receptors represent the latest innovation. These chimeras are uniquely tailored to degrade proteins that are membrane-bound and extracellular, encompassing approximately 40% of all proteome. Several novel LYTAC formulas have been developed recently, providing valuable insights for the design and development of therapeutic degraders. This review delineates the recent progresses of LYTAC technology, its practical applications, and the factors that dictate target degradation efficiency. The potential and emerging trends of this technology are discussed as well. LYTAC technology offers a promising avenue for targeted protein degradation, potentially revolutionizing the therapeutic landscape for numerous diseases.

Innate Immunity in Type 1 Diabetes.

Type 1 diabetes (T1D) results from the destruction of pancreatic β cells by the immune system, to which both pancreatic β-cell dysfunction and pathological activation of the immune system contribute. This paper is focused on understanding the modalities of this activation, and the genetic and environmental factors increasing its risk. Innate immunity has a critical role in the loss of self-tolerance and promotion of inflammation either directly using innate effector mechanisms or by providing activation signals to anti-islet adaptive autoimmunity. We provide an overview of various deleterious and protective roles of innate immunity in T1D inside pancreatic islets, regional lymph nodes, and distant locations such as the gut.

Endosomal escape mechanisms of extracellular vesicle-based drug carriers: lessons for lipid nanoparticle design.

The rise of biologics and RNA-based therapies challenges the limitations of traditional drug treatments. However, these potent new classes of therapeutics require effective delivery systems to reach their full potential. Lipid nanoparticles (LNPs) have emerged as a promising solution for RNA delivery, but endosomal entrapment remains a critical barrier. In contrast, natural extracellular vesicles (EVs) possess innate mechanisms to overcome endosomal degradation, demonstrating superior endosomal escape (EE) compared to conventional LNPs. This mini review explores the challenges of EE for lipid nanoparticle-based drug delivery, and offers insights into EV escape mechanisms to advance LNP design for RNA therapeutics. We compare the natural EE strategies of EVs with those used in LNPs and highlight contemporary LNP design approaches. By understanding the mechanisms of EE, we will be able to develop more effective drug delivery vehicles, enhancing the delivery and efficacy of RNA-based therapies.

Chronic NOD2 stimulation by MDP confers protection against parthanatos through M2b macrophage polarization in RAW264.7 cells

Innate immune cells show enhanced responsiveness to secondary challenges after an initial non-related stimulation (Trained Innate Immunity, TII). Acute NOD2 activation by Muramyl-Dipeptide (MDP) promotes TII inducing the secretion of pro-inflammatory mediators, while a sustained MDP-stimulation down-regulates the inflammatory response, restoring tolerance. Here we characterized in-vitro the response of murine macrophages to lipopolysaccharide (LPS) challenge under NOD2-chronic stimulation. RAW264.7 cells were trained with MDP (1 μg/ml, 48 h) and challenged with LPS (5 μg/ml, 24 h). Trained cells formed multinucleated giant cells with increased phagocytosis rates compared to untrained/challenged cells. They showed a reduced mitochondrial activity and a switch to aerobic glycolysis. TNF-α, ROS and NO were upregulated in both trained and untrained cultures (MDP+, MDP- cells, p > 0.05); while IL-10, IL-6 IL-12 and MHCII were upregulated only in trained cells after LPS challenge (MDP + LPS+, p < 0.05). A slight upregulation in the expression of B7.2 was also observed in this group, although differences were not statistically significant. MDP-training induced resistance to LPS challenge (p < 0.01). The relative expression of PARP-1 was downregulated after the LPS challenge, which may contribute to the regulatory milieu and to the innate memory mechanisms exhibited by MDP-trained cells. Our results demonstrate that a sustained MDP-training polarizes murine macrophages towards a M2b profile, inhibiting parthanatos. These results may impact on the development of strategies to immunomodulate processes in which inflammation should be controlled.

Macrophage-targeted versus free calcitriol as host-directed adjunct therapy against Mycobacterium tuberculosis infection in mice is bacteriostatic and mitigates tissue pathology

Host-directed therapy (HDT) with vitamin D in tuberculosis (TB) is beneficial only if the subject is deficient in vitamin D. We investigated pulmonary delivery of 1,25-dihydroxy vitamin D3 (calcitriol) in mice infected with Mycobacterium tuberculosis (Mtb). We made two kinds of dry powder inhalations (DPI)— soluble particles or poly(lactide) (PLA) particles. We compared treatment outcomes when infected mice were dosed with a DPI alone or as an adjunct to standard oral anti-TB therapy (ATT). Mice infected on Day 0 were treated between Days 28–56 and followed up on Days 57, 71, and 85. Neither DPI significantly reduced Mtb colony forming units (CFU) in the lungs. Combining DPI with ATT did not significantly augment bactericidal activity in the lungs, but CFU were 2-log lower in the spleen. CFU showed a rising trend on stopping treatment, sharper in groups that did not receive calcitriol. Lung morphology and histology improved markedly in animals that received PLA DPI; with or without concomitant ATT. Groups receiving soluble DPI had high mortality. DPI elicited cathelicidin, interleukin (IL)-1 and induced autophagy on days 57, 71, and 85. Macrophage-targeted calcitriol is therefore bacteriostatic, evokes innate microbicidal mechanisms, and mitigates pathology arising from the host response to Mtb.

Efficacy and Safety of Xylitol Nasal Irrigation after Functional Endoscopic Sinus Surgery: A Randomized Controlled Study

Xylitol is considered a naturally occurring antibacterial agent. It is generally believed to enhance the body’s own innate bactericidal mechanisms. It also provides anti-adhesive effects against both Streptococcus pneumoniae and Haemophilus influenza. This study was performed to evaluate the efficacy and safety of xylitol nasal irrigation in the postoperative care of functional endoscopic sinus surgery (FESS). Patients with chronic rhinosinusitis who received FESS were recruited and randomly assigned to two groups at one month post-surgery. Thirty-five patients in the xylitol group received 400 mL of 5% xylitol nasal irrigation daily for 2 months, while another 35 in the normal saline (NS) group received 400 mL of NS nasal irrigation daily for 2 months. Prior to FESS, as well as before and after nasal irrigation, sinonasal symptoms were assessed through the 22-item Sino-Nasal Outcome Test Questionnaire. The patients also underwent an endoscopic examination while undergoing nasal function tests, and a cytokine measurement of the nasal lavage and a bacterial culture from the middle meatus were performed. The safety of the nasal irrigation was assessed through any self-reported adverse events, the Eustachian Tube Dysfunction Patient Questionnaire and the eustachian tube function test. The endoscopic scores and olfactory threshold significantly decreased after xylitol irrigation when compared with those before irrigation. The prevalence of Staphylococcus aureus in the nasal secretions also decreased significantly after xylitol irrigation. The amounts of Interleukin-5 and Interleukin-17A were significantly increased in the nasal lavage after xylitol irrigation. No side effects, including those related to eustachian tube function, were seen after nasal irrigation in both groups. Our results showed that xylitol nasal irrigation was both beneficial and safe during the postoperative care of FESS.

Polymerized Salicylic Acid Microparticles Reduce the Progression and Formation of Human Neutrophil Extracellular Traps (NET)s.

Neutrophils can contribute to inflammatory disease propagation via innate mechanisms intended for inflammation resolution. For example, neutrophil extracellular traps (NETs) are necessary for trapping pathogens but can contribute to clot formation and blood flow restriction, that is, ischemia. Currently, no therapeutics in the clinic directly target NETs despite the known involvement of NETs contributing to mortality and increased disease severity. Vascular-deployed particle-based therapeutics are a novel and robust alternative to traditional small-molecule drugs by enhancing drug delivery to cells of interest. This work designs a high-throughput assay to investigate the immunomodulatory behavior and functionality of salicylic acid-based polymer-based particle therapeutics against NETosis in human neutrophils. Briefly, this work finds that polymeric composition plays a role, and particle size can also influence rates of NETosis. Salicylate-based polymeric (Poly-SA) particles are found to functionally inhibit NETosis depending on the particle size and concentration exposed to neutrophils. This work demonstrates the high throughput method can help fast-track particle-based therapeutic optimization and design, more efficiently preparing this innovative therapeutics for the clinic.

Effects of dietary curcumin nano-micelles on performance, biological responses, and thermal stress resilience in heat-stressed fattening lambs across varying temperature-humidity index conditions: Implications for climate change

Heat stress poses a significant challenge to sheep farming in arid and semi-arid regions, impacting growth performance, health, and physiological responses. While sheep have innate mechanisms to manage heat stress, prolonged exposure impairs their performance and health. This study evaluated the influence of varying doses of Curcumin Nano-Micelle (CNM) on heat-stressed fattening lambs in northeastern Iran over three months, examining the relationship between CNM doses and growth performance, feeding behavior, physiological responses, immune function, and antioxidant status. Thirty-two crossbred male lambs were included in a completely randomized design with four treatments and eight replications. The experimental treatments were as follows: 1) CTRL: No dietary inclusion of CNM, (control group); 2) T20: Dietary inclusion of 20 mg of CNM per head per day; 3) T40: Dietary inclusion of 40 mg of CNM per head per day; and 4) T80: Dietary inclusion of 80 mg of CNM per head per day. The results revealed that dietary supplementation with 20 and 40 mg of CNM significantly improved live body weight, weight gain, average daily gain (ADG), and feed conversion ratio (FCR) compared to the control treatment. Regression analysis demonstrated quadratic models between growth performance parameters and the Temperature-Humidity Index (THI), indicating a correlation between CNM doses and the animals' responses to heat stress. Regarding eating behavior, CNM doses of 40 and 80 mg/day significantly reduced eating time while increasing ruminating time. Blood analysis indicated significant reductions in glucose levels across all treatments, with T40 significantly reducing both cholesterol and triglyceride (TG) levels. Additionally, CNM supplementation decreased serum malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, indicating enhanced antioxidant status. Physiological responses were influenced by CNM, notably reducing rectal temperature (RT), skin temperature (ST), respiration rate (RR), while pulse rate (PR) increased across various time intervals, particularly in the T80 group. This study demonstrates that CNM supplementation can enhance performance, physiological responses, and antioxidant status in heat-stressed fattening lambs, highlighting its potential to mitigate heat stress effects in sheep farming.

음양균형의학으로서의 턱관절균형의학 개요

Objectives Temporomandibular Joint Balancing Medicine (TBM) is a relatively new approach to the temporomandibular joint(TMJ) perceived as a key to the whole-body balance. This study aimed to briefly review concepts, history, and research reports on TBM with a focus on the yin-yang balance concept. Methods A narrative review was performed regarding TBM referring to published literature. Results TBM encompassed a variety of innovative clinical techniques for evaluation and improvement of the balance of the TMJ, nervous system, and meridian system featuring the integration between TMJ and body. Its target ranged from diseases to subclinical functional imbalances. TBM harnessed the postural balance of TMJ as a central tool to manipulate postural proprioception and thereby stimulate the innate healing mechanism of the whole body. Conclusions TBM was based on the concept of yin-yang balance and provided an integrated approach to disease treatment as well as to the improvement of subclinical health conditions.

КОГНИТИВНЫЙ НЕОАССОЦИАНИЗМ:РОЛЬ ОТРИЦАТЕЛЬНЫХ ЭМОЦИЙ

The relevance of the topic “Cognitive neo-associationism: the role of negative emotions” is that, despite the time, the question of aggression and the way to calm down still stands and has not been completely resolved due to the fact that it is impossible to completely select an individual plan for combating aggression. Methods with elements of art, relaxation exercises and even sports were used as the main solutions to the problem. In the aspect of cognitive assessment, basic and suprabasic emotions are considered. If basic emotions are triggered by innate triggers, then supra-basic ones are triggered by those acquired during the life of a particular person. Superbasic or socialized emotions most often have a cognitive nature of origin and their appearance in the psyche. Such emotions are conscious in nature, since they appear upon the fact of a cognitive assessment of the stimulus; in turn, the appearance of basic emotions based on innate stimuli is most often not realized by a person. The purpose of the study was to overcome constructs in the scientific literature about the dominance of cognitive mechanisms of the origin of emotions. The object of the study was emotions and the nature of their origin. The subject of the study was a critique of the cognitive approach to the origin of emotions and the substantiation of the importance of the biological approach, where an important role is given to the innate and genetic mechanisms of the appearance of emotions. The methodological basis of the study was the analysis of scientific research on the problem of the nature and appearance of basic emotions in the psyche.

Learning Fast and Slow: A Redux of Levels of Learning in General Autonomous Intelligent Agents

Autonomous intelligent agents, including humans, operate in a complex, dynamic environment that necessitates continuous learning. We revisit our thesis that proposes that learning in human-like agents can be categorized into two levels: Level 1 (L1) involving innate and automatic learning mechanisms, while Level 2 (L2) comprises deliberate strategies controlled by the agent. Our thesis draws from our experiences in building artificial agents with complex learning behaviors, such as interactive task learning and open-world learning.

Toward Autonomy: Metacognitive Learning for Enhanced AI Performance

Large Language Models (LLMs) lack robust metacognitive learning abilities and depend on human-provided algorithms and prompts for learning and output generation. Metacognition involves processes that monitor and enhance cognition. Learning how to learn - metacognitive learning - is crucial for adapting and optimizing learning strategies over time. Although LLMs possess limited metacognitive abilities, they cannot autonomously refine or optimize these strategies. Humans possess innate mechanisms for metacognitive learning that enable at least two unique abilities: discerning which metacognitive strategies are best and automatizing learning strategies. These processes have been effectively modeled in the ACT-R cognitive architecture, providing insights on a path toward greater learning autonomy in AI. Incorporating human-like metacognitive learning abilities into AI could potentially lead to the development of more autonomous and versatile learning mechanisms, as well as improved problem-solving capabilities and performance across diverse tasks.

Face detection mechanisms: Nature vs. nurture.

For many animals, faces are a vitally important visual stimulus. Hence, it is not surprising that face perception has become a very popular research topic in neuroscience, with ca. 2000 papers published every year. As a result, significant progress has been made in understanding the intricate mechanisms underlying this phenomenon. However, the ontogeny of face perception, in particular the role of innate predispositions, remains largely unexplored at the neural level. Several influential studies in monkeys have suggested that seeing faces is necessary for the development of the face-selective brain domains. At the same time, behavioural experiments with newborn human babies and newly-hatched domestic chicks demonstrate that a spontaneous preference towards faces emerges early in life without pre-existing experience. Moreover, we were recently able to record face-selective neural responses in the brain of young, face-naïve chicks, thus demonstrating the existence of an innate face detection mechanism. In this review, we discuss these seemingly contradictory results and propose potential experimental approaches to resolve some of the open questions.

A method to mitigate cyber exploits on automatic dependent surveillance-broadcast (ADS-B) data transmissions

PurposeAutomatic dependent surveillance-broadcast (ADS-B) is the foundational technology of the next generation air transportation system defined by Federal Aviation Authority and is one of the most precise ways for tracking aircraft position. ADS-B is intended to provide greater situational awareness to the pilots by displaying the traffic information like aircraft ID, altitude, speed and other critical parameters on the Cockpit Display of Traffic Information displays in the cockpit. Unfortunately, due to the initial proposed nature of ADS-B protocol, it is neither encrypted nor has any other innate security mechanisms, which makes it an easy target for malicious attacks. The system is vulnerable to various active and passive attacks like message ingestion, message deletion, eavesdropping, jamming, etc., which has become an area of concern for the aviation industry. The purpose of this study is to propose a method based on modified advanced encryption standard (AES) algorithm to secure the ADS=B messages and increase the integrity of ADS-B data transmissions.Design/methodology/approachThough there are various cryptographic and non-cryptographic methods proposed to secure ADS-B data transmissions, it is evident that most of these systems have limitations in terms of cost, implementation or feasibility. The new proposed method implements AES encryption techniques on the ADS-B data on the sender side and correlated decryption mechanism at the receiver end. The system is designed based on the flight schedule data available from any flight planning systems and implementing the AES algorithm on the ADS-B data from each aircraft in the flight schedule.FindingsThe suitable hardware was developed using Raspberry pi, ESP32 and Ra-02. Several runs were done to verify the original message, transmitted data and received data. During transmission, encryption algorithm was being developed, which has got very high secured transmission, and during the reception, the data was secured. Field test was conducted to validate the transmission and quality. Several trials were done to validate the transmission process. The authors have successfully shown that the ADS-B data can be encrypted using AES algorithm. The authors are successful in transmitting and receiving the ADS-B data packet using the discussed hardware and software methodology. One major advantage of using the proposed solution is that the information received is encrypted, and the receiver ADS-B system can decrypt the messages on the receiving end. This clearly proves that when the data is received by an unknown receiver, the messages cannot be decrypted, as the receiver is not capable of decrypting the AES-authenticated messages transmitted by the authenticated source. Also, AES encryption is highly unlikely to be decrypted if the encryption key and the associated decryption key are not known.Research limitations/implicationsImplementation of the developed solution in actual onboard avionics systems is not within the scope of this research. Hence, assessing in the real-time distances is not covered.Social implicationsThe authors propose to extend this as a software solution to the onboard avionics systems by considering the required architectural changes. This solution can also bring in positive results for unmanned air vehicles in addition to the commercial aircrafts. Enhancement of security to the key operational and navigation data elements is going to be invaluable for future air traffic management and saving lives of people.Originality/valueThe proposed solution has been practically implemented by developing the hardware and software as part of this research. This has been clearly brought out in the paper. The implementation has been tested using the actual ADS-B data/messages received from using the ADS-B receiver. The solution works perfectly, and this brings immense value to the aircraft-to-aircraft and aircraft-to-ground communications, specifically while using ADS-B data for communicating the position information. With the proposed architecture and minor software updates to the onboard avionics, this solution can enhance safety of flights.

Maintenance of homeostasis by TLR4 ligands.

Immunotherapy is renowned for its capacity to elicit anti-infective and anti-cancer effects by harnessing immune responses to microbial components and bolstering innate healing mechanisms through a cascade of immunological reactions. Specifically, mammalian Toll-like receptors (TLRs) have been identified as key receptors responsible for detecting microbial components. The discovery of these mammalian Toll-like receptors has clarified antigen recognition by the innate immune system. It has furnished a molecular foundation for comprehending the interplay between innate immunity and its anti-tumor or anti-infective capabilities. Moreover, accumulating evidence highlights the crucial role of TLRs in maintaining tissue homeostasis. It has also become evident that TLR-expressing macrophages play a central role in immunity by participating in the clearance of foreign substances, tissue repair, and the establishment of new tissue. This macrophage network, centered on macrophages, significantly contributes to innate healing. This review will primarily delve into innate immunity, specifically focusing on substances targeting TLR4.

Abstract LB062: ADT3_A potential first-in-class Vδ1-engager for in situ activation of Vδ1 γδ T cells and enhanced cytotoxicity towards solid tumors

Abstract Gamma delta (γδ) T cells are crucial in stress surveillance for infections and cancer. Studies have shown that tumour-infiltrating γδ T cells are a positive prognostic factor in cancer therapy. While γδ T cells share many characteristics with their αβ T cell counterpart, such as cytotoxic effector functions, they express a distinct TCR that is composed of a γ and a δ chain, belong to the HLA-class-I unrestricted immune cell subset with the ability to discriminate and specifically kill tumor cells via recognition of tumor stress ligands. Clinical trials using Vδ1 γδ T cell therapies have demonstrated promising results in Ph 1 trials, with early signs of favorable efficacy and safety profile.ADT3, is a novel bispecific engager that activates tissue-resident Vδ1+ T cells via (Epidermal Growth Factor Receptor) EGFR crosslinking on tumor cells. VD1 T cells isolated from skin biopsies, when activated, enhance the selective killing of EGFR positive tumor cells through innate mechanisms that recognize stress ligands that are otherwise absent on healthy cells. As a bispecific engager, ADT3 preserves high affinity binding to VD1 TCR through the Fab end of the molecule, and binding to two EGFR binding sites via the modified Fc domain. Crosslinking of VD1 and EGFR+ tumor cells with ADT3, mediates a series of events leading to proliferation of VD1 cells, upregulation of activation markers, CD107a degranulation and secretion of chemokines and cytokines (such as TNFa and IFNg) and tumor kill as determined by its potent cytotoxic activity in a T-cell dependent cellular cytotoxicity assay (TDCC). Apart from direct tumor kill, the secretion of such cytokines and chemokines via ADT3 activation are required for induction of immune orchestration of non-Vδ1 immune cells to enhance tumor kill. Preclinical data supports future clinical entry of ADT3, and IND enabling studies are in progress Citation Format: Joshua Freedman, Georgia Stevens, Julie Julie Hoong, Mihirban Tuna, Yaoyao Shi, Kathy J. Seidl, Katherine Galvin, Andrew Hutton, Antara Banerjee. ADT3_A potential first-in-class Vδ1-engager for in situ activation of Vδ1 γδ T cells and enhanced cytotoxicity towards solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB062.

Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials

IntroductionAnifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using...

Engineering fibronectin-templated multi-component fibrillar extracellular matrices to modulate tissue-specific cell response

Cells assemble fibronectin, the major extracellular matrix (ECM) protein, into fibrillar matrices, which serve as 3D architectural scaffolds to provide, together with other ECM proteins tissue-specific environments. Although recent approaches enable to bioengineer 3D fibrillar fibronectin matrices in vitro, it remains elusive how fibronectin can be co-assembled with other ECM proteins into complex 3D fibrillar matrices that recapitulate tissue-specific compositions and cellular responses. Here, we introduce the engineering of fibrillar fibronectin-templated 3D matrices that can be complemented with other ECM proteins, including vitronectin, collagen, and laminin to resemble ECM architectures observed in vivo. For the co-assembly of different ECM proteins, we employed their innate fibrillogenic mechanisms including shear forces, pH-dependent electrostatic interactions, or specific binding domains. Through recapitulating various tissue-specific ECM compositions and morphologies, the large scale multi-composite 3D fibrillar ECM matrices can guide fibroblast adhesion, 3D fibroblast tissue formation, or tissue morphogenesis of epithelial cells. In other examples, we customize multi-composite 3D fibrillar matrices to support the growth of signal propagating neuronal networks and of human brain organoids. We envision that these 3D fibrillar ECM matrices can be tailored in scale and composition to modulate tissue-specific responses across various biological length scales and systems, and thus to advance manyfold studies of cell biological systems.