Complex Biological Environments Research Articles

Responsive Nanomaterial Delivery Systems for Pancreatic Cancer Management

AbstractPancreatic cancer is characterized by a high mortality rate and unfavorable prognosis. This is primarily attributed to poor accumulation of therapeutic agents at the target site due to the presence of a highly complex tumor microenvironment surrounding the pancreatic cancer tissue. However, a promising avenue for targeted drug delivery has emerged in the form of stimuli‐responsive materials. These advanced nanocarriers, encompassing both external and internal stimuli‐responsive nanoparticles, can be formulated to control the release of therapeutic agents precisely in response to specific activation. By harnessing external stimuli such as light, ultrasound, or magnetic fields, as well as intrinsic biological triggers including pH, redox potential, hypoxia, and temperature, these nanomaterials exhibit ‘intelligent’ and selective responses within complex biological environments. These responsive nanoparticles have been shown to address challenges associated with poor vascularity and thick desmoplastic stromal layers, which are hallmarks of pancreatic cancer, by promoting enhanced drug accumulation and release at the target site relative to conventional therapy. This work explores the design strategies for advanced stimuli‐responsive nanomaterials, integrating both internal and external stimuli, with the potential to enhance drug delivery efficacy in pancreatic cancer. It addresses the challenges and prospects in their development and offers insights for future clinical applications.

Supramolecular fluorescence sensor array used for the analysis of tyrosine kinase inhibitors in biological fluids and cell imaging

Tyrosine kinase inhibitors (TKIs) are commonly used in tumor targeting therapy. However, the rapid analysis of TKIs remains a significant challenge, especially in complex biological fluid environments. In this work, we have constructed a supramolecular fluorescence sensor array based on a cucurbituril-dye host-guest complex. The binding affinity between the three complexes and each TKI is different, resulting in different cross-response signals of the complexes to the fluorescence of each TKI. Combined with linear discriminant analysis(LDA), five kinds of TKIs can be well identified. The supramolecular fluorescence sensor array could accurately identify and distinguish the five TKIs in water and could classify mixtures containing different concentrations of TKIs in serum. The concentration and Factor 1 exhibited a good linear relationship and the detection limit (LOD) was as low as 10−7 mol L−1. The method has good reproducibility and stability. In addition, the differentiation of four clinical concentrations of first-generation TKIs further validated the potential application of arrays in drug monitoring. Finally, our proposed array enabled drug imaging in living cells. Our array platform provided the foundation for the rapid and easy monitoring of 4-anilinoquinazoline TKIs.

PCNA as Protein-Based Nanoruler for Sub-10nm Fluorescence Imaging.

Super-resolution microscopy has revolutionized biological imaging enabling direct insight into cellular structures and protein arrangements with so far unmatched spatial resolution. Today, refined single-molecule localization microscopy methods achieve spatial resolutions in the one-digit nanometer range. As the race for molecular resolution fluorescence imaging with visible light continues, reliable biologically compatible reference structures will become essential to validate the resolution power. Here, PicoRulers (protein-based imaging calibration optical rulers), multilabeled oligomeric proteins designed as advanced molecular nanorulers for super-resolution fluorescence imaging are introduced. Genetic code expansion (GCE) is used to site-specifically incorporate three noncanonical amino acids (ncAAs) into the homotrimeric proliferating cell nuclear antigen (PCNA) at 6nm distances. Bioorthogonal click labeling with tetrazine-dyes and tetrazine-functionalized oligonucleotides allows efficient labeling of the PicoRuler with minimal linkage error. Time-resolved photoswitching fingerprint analysis is used to demonstrate the successful synthesis and DNA-based points accumulation for imaging in nanoscale topography (DNA-PAINT) is used to resolve 6nm PCNA PicoRulers. Since PicoRulers maintain their structural integrity under cellular conditions they represent ideal molecular nanorulers for benchmarking the performance of super-resolution imaging techniques, particularly in complex biological environments.

Villous 3D nanoconfined flexible carbon fibers-based electrode toward dopamine electrochemical detection

Flexible sensing interfaces for the analysis of biological samples are crucial to realize human dopamine health detection; thus, flexible sensors for biomolecular analysis have attracted considerable attention. Herein, we report a villous three-dimensional (3D) nanoconfined carbon fibers-based flexible sensor for the electrochemical analysis of dopamine (DA). Carbon nanofibers-modified carbon fibers (CNFs/CFs) with abundant nanochannels were obtained by chemical vapor deposition, and the sensing platform achieved ultra-sensitive analysis owing to the construction of nanoconfined spaces. The combination of a 3D network structure and surface N doping (N-CNFs/CFs) significantly enhanced the local enrichment of DA, thus providing a basis for ultrasensitive detection of DA. Furthermore, modified Au nanoparticles (Au/N-CNFs/CFs) exhibited s enhanced the electrocatalytic ability and electron transfer efficiency. The detection limit for DA reached 0.087 μM (S/N = 3) in the linear range of 1–800 μM. Under optimal conditions, the designed electrode material shows good performance in complex biological environments, including human serum, urine, and artificial cerebrospinal fluid). The developed Au/N-CNFs/CFs therefore provide a portable and efficient sensor for the clinical detection of biomolecules.

Novel NIR fluorescent probe for hypochlorite ion detection in biological systems

This study presents the synthesis and application of a novel fluorescent probe, NR-ClO, for the detection of hypochlorite ion (ClO–) in biological systems. The probe was synthesized through a nucleophilic substitution reaction between Nile red and dimethylcarbamothioic chloride. The synthesized probe had high sensitivity and selectivity towards ClO–, with a detection limit of 75 nM and a linear range of 0.1–200 μM. The probe's efficacy was validated through in vitro studies using HepG2 cells and in vivo experiments using a mouse model of rheumatoid arthritis. The findings demonstrate that the NR-ClO probe is a promisingly reliable tool for real-time monitoring of ClO– in complex biological environments.

The origins of nonideality exhibited by monoclonal antibodies and Fab fragments in human serum.

The development of therapeutic antibodies remains challenging, time-consuming, and expensive. A key contributing factor is a lack of understanding of how proteins are affected by complex biological environments such as serum and plasma. Nonideality due to attractive or repulsive interactions with cosolutes can alter the stability, aggregation propensity, and binding interactions of proteins in solution. Fluorescence correlation spectroscopy (FCS) can be used to measure apparent second virial coefficient (B2,app ) values for therapeutic and model monoclonal antibodies (mAbs) that capture the nature and strength of interactions with cosolutes directly in undiluted serum and similar complex biological media. Here, we use FCS-derived B2,app measurements to identify the components of human serum responsible for nonideal interactions with mAbs and Fab fragments. Most mAbs exhibit neutral or slightly attractive interactions with intact serum. Generally, mAbs display repulsive interactions with albumin and mildly attractive interactions with IgGs in the context of whole serum. Crucially, however, these attractive interactions are much stronger with pooled IgGs isolated from other serum components, indicating that the effects of serum nonideality can only be understood by studying the intact medium (rather than isolated components). Moreover, Fab fragments universally exhibited more attractive interactions than their parental mAbs, potentially rendering them more susceptible to nonideality-driven perturbations. FCS-based B2,app measurements have the potential to advance our understanding of how physiological environments impact protein-based therapeutics in general. Furthermore, incorporating such assays into preclinical biologics development may help de-risk molecules and make for a faster and more efficient development process.

Control of Luminescence and Interfacial Properties as Perspective for Upconversion Nanoparticles.

Near-infrared (NIR) light is highly suitable for studying biological systems due to its minimal scattering and lack of background fluorescence excitation, resulting in high signal-to-noise ratios. By combining NIR light with lanthanide-based upconversion nanoparticles (UCNPs), upconversion is used to generate UV or visible light within tissue. This remarkable property has gained significant research interest over the past two decades. Synthesis methods are developed to produce particles of various sizes, shapes, and complex core-shell architectures and new strategies are explored to optimize particle properties for specific bioapplications. The diverse photophysics of lanthanide ions offers extensive possibilities to tailor spectral characteristics by incorporating different ions and manipulating their arrangement within the nanocrystal. However, several challenges remain before UCNPs can be widely applied. Understanding the behavior of particle surfaces when exposed to complex biological environments is crucial. In applications where deep tissue penetration is required, such as photodynamic therapy and optogenetics, UCNPs show great potential as nanolamps. These nanoparticles can combine diagnostics and therapeutics in a minimally invasive, efficient manner, making them ideal upconversion probes. This article provides an overview of recent UCNP design trends, highlights past research achievements, and outlines potential future directions to bring upconversion research to the next level.

FAST SOLVER FOR DIFFUSIVE TRANSPORT TIMES ON DYNAMIC INTRACELLULAR NETWORKS.

The transport of particles in cells is influenced by the properties of intracellular networks they traverse while searching for localized target regions or reaction partners. Moreover, given the rapid turnover in many intracellular structures, it is crucial to understand how temporal changes in the network structure affect diffusive transport. In this work, we use network theory to characterize complex intracellular biological environments across scales. We develop an efficient computational method to compute the mean first passage times for simulating a particle diffusing along two-dimensional planar networks extracted from fluorescence microscopy imaging. We first benchmark this methodology in the context of synthetic networks, and subsequently apply it to live-cell data from endoplasmic reticulum tubular networks.

Effect of Protonation on the Molecular Structure of Adenosine 5'-Triphosphate: A Combined Theoretical and Near Edge X-ray Absorption Fine Structure Study.

The present work combines the near edge X-ray absorption mass spectrometry of a protonated adenosine 5'-triphosphate (ATP) molecule isolated in an ion trap with (time-dependent) density functional theory calculations. Our study unravels the effect of protonation on the ATP structure and its spectral properties, providing structure-property relationships at atomistic resolution for protonated ATP (ATPH) isolated in the gas-phase conditions. On the other hand, the present C and N K-edge X-ray absorption spectra of isolated ATPH appear closely like those previously reported for solvated ATP at low pH. Therefore, the present work should be relevant for further investigation and modeling of structure-function properties of protonated adenine and ATP in complex biological environments.

Customized fluorescent probe for peering into the expression of butyrylcholinesterase in thyroid cancer

BackgroundThyroid cancer has been increasingly prevalent in recent years. The main diagnostic methods for thyroid are B-ultrasound scan, serum detection and puncture detection. However, these methods are invasive and complex. It is a pressing need to develop non-invasive or minimally invasive methods for thyroid cancer diagnosis. Fluorescence method as a non-invasive detection method has attracted much attention. Butyrylcholinesterase (BChE) is a common enzyme in the human body, and many diseases affect its reduction. We found that BChE is also a marker for thyroid cancer. Therefore, it is of certain clinical value to explore the expression of BChE in thyroid cancer cells through a customized fluorescent probe to provide valuable experimental data and clues for studying the expression of thyroid cancer marker to reflect thyroid status. ResultsIn this study, we customized a fluorescent probe named Kang-BChE, which is easy to synthesize with a high yield. The experimental results show that the probe Kang-BChE can detect BChE in the linear range of 0–900 U L−1 (R2 = 0.9963), and the detection limit is as low as 3.93 U L−1 (λex/em = 550/689 nm). In addition, Kang-BChE probes have low cytotoxicity, good specificity, and can completely eliminate interference from acetylcholinesterase (AChE). Kang-BChE showed excellent stability in the detection of complex biological samples in serum recovery experiments (95.64–103.12 %). This study was the first time using Kang-BChE to study the low expression of BChE in thyroid cancer cells (Tpc-1 cells). In addition, we observed that H2O2 concentration in Tpc-1 cells was positively correlated with BChE activity. SignificanceKang-BChE is expected to be an important tool for monitoring the change of BChE content in complex biological environments due to its excellent performance. Kang-BChE can also be used to explore the influence of molecules in more organisms on the change of BChE content due to its excellent anti-interference ability. We expect that Kang-BChE can play a significant role in the clinical diagnosis and treatment of thyroid cancer.

Antiemetic effects of sclareol, possibly through 5-HT3 and D2 receptor interaction pathways: In-vivo and in-silico studies

BackgroundEmesis is a complex physiological phenomenon that serves as a defense against numerous toxins, stressful situations, adverse medication responses, chemotherapy, and movement. Nevertheless, preventing emesis during chemotherapy or other situations is a significant issue for researchers. Hence, the majority view contends that successfully combining therapy is the best course of action. In-vivo analysis offers a more comprehensive grasp of how compounds behave within a complex biological environment, whereas in-silico evaluation refers to the use of computational models to forecast biological interactions. ObjectivesThe objectives of the present study were to evaluate the effects of Sclareol (SCL) on copper sulphate-induced emetic chicks and to investigate the combined effects of these compounds using a conventional co-treatment approach and in-silico study. MethodsSCL (5, 10, and 15 mg/kg) administered orally with or without pre-treatment with anti-emetic drugs (Ondansetron (ODN): 24 mg/kg, Domperidone (DOM): 80 mg/kg, Hyoscine butylbromide (HYS): 100 mg/kg, and Promethazine hydrochloride (PRO): 100 mg/kg) to illustrate the effects and the potential involvement with 5HT3, D2, M3/AChM, H1, or NK1 receptors by SCL. Furthermore, an in-silico analysis was conducted to forecast the role of these receptors in the emetic process. ResultsThe results suggest that SCL exerted a dose-dependent anti-emetic effect on the chicks. Pretreatment with SCL-10 significantly minimized the number of retches and lengthened the emesis tendency of the experimental animals. SCL-10 significantly increased the anti-emetic effects of ODN and DOM. However, compared to the ODN-treated group, (SCL-10 + ODN) group considerably (p < 0.0001) extended the latency duration (109.40 ± 1.03 s) and significantly (p < 0.01) decreased the number of retches (20.00 ± 0.70), indicating an anti-emetic effect on the test animals. In in-silico analysis, SCL exhibited promising binding affinities with suggesting receptors. ConclusionSCL-10 exerted an inhibitory-like effect on emetic chicks, probably through the interaction of the 5HT3 and D2 receptors. Further studies are highly appreciated to validate this study and determine the precise mechanism(s) behind the anti-emetic effects of SCL. We expect that SCL-10 may be utilized as an antiemetic treatment in a single dosage form or that it may function as a synergist with other traditional medicines.

Bletilla Striata polysaccharides thermosensitive gel for photothermal treatment of bacterial infection

Skin is the most important defense shield which touched external environment directly. Effectively clearing microbes in infected wound via non-antibiotic therapy is crucial for the promotion of recovery in complex biological environments, and the wound healing is a crucial process after sterilization to avoid superinfection. Herein, a kind of Prussian blue-based photothermal responsive gel, Bletilla striata polysaccharide-mingled, isatin-functionalized Prussian blue gel (PB-ISA/BSP gel) was reported for effective treatment of bacterial infection and wound healing. The introduction of effective components of traditional Chinese medicine (TCM), isatin (ISA), enhanced the efficiency of sterilization synergistically. Furthermore, the process of wound healing was promoted by Bletilla striata polysaccharides (BSP). PB-ISA@BSP had a considerable antibacterial rate with 98.5 % under an 808 nm laser for 10 min in vitro. Besides, PB-ISA/BSP gel showed an effective antibacterial efficacy in vivo and a fast wound healing rate as well. The as-prepared functional particles can invade and destroy bacteria membrane to kill microbes. This work highlights that PB-ISA/BSP gel is a promising antibacterial agent based on synergistically enhanced photothermal effect and wound healing promotion ability and provides inspiration for future therapy based on the synergy between photothermal agent and active components in TCM.

Chemical Amplification-Enabled Topological Modification of Nucleic Acid Aptamers for Enhanced Cancer-Targeted Theranostics.

Site-specific chemical conjugation has long been a challenging endeavor in the field of ligand-directed modification to produce homogeneous conjugates for precision medicine. Here, we develop a chemical amplification-enabled topological modification (Chem-ATM) methodology to establish a versatile platform for the programmable modification of nucleic acid aptamers with designated functionalities. Differing from conventional conjugation strategies, a three-dimensional artificial base is designed in Chem-ATM as a chemical amplifier, giving access to structurally and functionally diversified conjugation of aptamers, with precise control over loading capacity but in a sequence-independent manner. Meanwhile, the sp3 hybridized atom-containing amplifier enables planar-to-stereo conformational transformation of the entire conjugate, eliciting high steric hindrance against enzymatic degradation in complex biological environments. The versatility of Chem-ATM is successfully demonstrated by its delivery of anticancer drugs and imaging agents for enhanced therapy and high-contrast noninvasive tumor imaging in xenograft and orthotopic tumor models. This study offers a different perspective for ligand-directed chemical conjugation to enrich the molecular toolbox for bioimaging and drug development.

Optical Nanosensors for the Detection of Quaternary Ammonium Compounds

Quaternary ammonium compounds (QACs) are common active ingredients in chemical disinfectants, household cleaners, cosmetics, pesticides, etc. Recently QACs have been detected in human blood and breast milk during the COVID-19 pandemic. Humans can be exposed to QACs through dermal adsorption during application, hand-to-mouth ingestion of disinfectant residues, and inhalation of indoor air upon treatment with disinfectant spray. Exposure to these chemicals can cause respiratory illness such as asthma and chronic obstructive pulmonary disease, increase inflammatory cytokines, decrease mitochondrial function, and disrupt cholesterol biosynthesis. However, the complete biological fate of QACs is currently unknown. Therefore, a real-time continuous monitoring system in complex biological environments is crucial to learn the long-term effects of QACs on human health.Photoluminescent single-walled carbon nanotubes (SWCNTs) are great candidates for developing optical probes to monitor biological systems due to their outstanding photophysical properties in the tissue-transparent near-infrared spectral region, high sensitivity, and high stability. Furthermore, nanotube-based sensors exhibit a great potential for an implantable, real-time, wireless optical detection technology. Herein, we developed a carbon nanotube-based optical sensor for the detection of QACs in complex solution. Our findings from this research could provide a basis for engineering an optical detection technology to gain insight on the long-term effects of QACs to human health.

Improved Sensitivity and Selectivity of Glutathione Detection through Target-Driven Electron Donor Generation in Photoelectrochemical Electrodes.

Glutathione (GSH) plays a vital role in many physiological processes, and its abnormal levels have been found to be associated with several diseases. In contrast to traditional methods using electron donor-containing electrolytes for photoelectrochemical (PEC) sensing, in this study, a target-driven electron donor generation in a PEC electrode was developed to detect GSH. Using well-aligned TiO2 nanotube arrays (TNTs) as the PEC substrate, mesoporous MIL-125(Ti) was grown in the TNTs through an in situ solvothermal method and subsequent two-step annealing treatment. The accommodation capacity of mesoporous MIL-125(Ti) allows a well loading of cystine and Pt nanoclusters (NCs). Taking advantage of the specific cleavage ability of disulfide bonds by GSH, cystine was converted to cysteine, which served as the electron donor for the PEC process. Benefiting from the confinement effect of mesoporous MIL-125(Ti), cysteine was effectively oxidized to cysteine sulfinic acid by the photogenerated holes. Importantly, the highly active Pt NCs decorated in the mesopores not only improved the charge transfer but also accelerated the above oxidation reaction. The synergistic effect of these factors enabled the efficient separation of the photogenerated electron-hole pairs, which induced a significant photocurrent increase and in turn led to the high-sensitivity detection of GSH. Consequently, the proposed PEC biosensor exhibited excellent performance in the detection of GSH in serum specimens. The target-driven electron donor generation designed in this study might open a new route for developing sensitive and selective PEC biosensors with application in complex biological environments.

A narrative review: progress in transition metal-mediated bioorthogonal catalysis for the treatment of solid tumors.

Transition metals are commonly used catalysts in bioorthogonal chemistry and have attracted extensive attention in biochemistry because of their efficient catalytic performance. In recent years, transition metal-mediated cycloaddition reactions, bond cleavage, and formation reactions are being actively explored for tumor treatment. However, the direct application of transition metals in complex biological environments has several problems, including poor solubility, toxicity, and easy inactivation. The combination of transition metals and nanomaterials can solve those problems by playing a bioorthogonal catalytic role in tumor treatment. In this review, we summarize some research on the application of transition metals modified by nanomaterials in tumor therapy and discuss the potential and challenges of transition metal-mediated bioorthogonal therapy in comprehensive tumor therapy. English literature on transition metal in cancer treatment was searched in PubMed and Web of Science. The main search terms were "cancer treatment", "bioorthogonal reaction", "transition metal", "bioorthogonal catalysis", etc. This review summarizes research on several major transition metals that can be used for bioorthogonal catalysis with the assistance of nanomaterials in anti-tumor therapy. In addition, bioorthogonal catalysis is a new supplement to antitumor therapy. We have compiled the potential challenges of the clinical application of transition metal-based nanocatalysts, which lays the foundation for future research related to medicinal chemistry and targeted cancer therapy. Most of the transition metals still have a lot of room for exploration in cancer treatment research. We still need more research to confirm the feasibility of in vivo and clinical trials.

Construction of an autocatalysis-driven DNA circuit for highly efficient detection of H5N1 oligonucleotide

H5N1 is a highly pathogenic avian influenza virus (AIV) that is a significant risk to both poultry production and human health. The sensitive and reliable determination of H5N1 is thus highly desirable for early antiviral therapy and controlling the outbreak. Isothermal DNA circuits have afforded a promising tool for molecular sensing in complex biological environments, yet are always constrained by their low amplification depth and insufficient signal gain. Herein, a simple-yet-robust autocatalytic DNA circuit (ADC) was devised for highly efficient H5N1 DNA analysis through the synergistic catalysis of catalytic hairpin assembly (CHA) and rolling circle amplification (RCA). The trigger-activated RCA circuit can generate numerous repeated initiators for stimulating the CHA transducer. Meanwhile, the initiator-stimulated CHA circuit can produce the re-assembled RCA trigger to reversely motivate the RCA system. The synergistic cross-activation between the RCA and CHA amplicon can achieve progressive reaction acceleration and exponentially amplified signal gain. The ADC system is highly versatile and capable of reliably detecting H5N1 DNA in buffer and biological samples with high performance, highlighting its great promise for low-abundance biomolecule sensing and early disease diagnosis.

Regulation strategies for two-output biomolecular networks.

Feedback control theory facilitates the development of self-regulating systems with desired performance which are predictable and insensitive to disturbances. Feedback regulatory topologies are found in many natural systems and have been of key importance in the design of reliable synthetic bio-devices operating in complex biological environments. Here, we study control schemes for biomolecular processes with two outputs of interest, expanding previously described concepts based on single-output systems. Regulation of such processes may unlock new design possibilities but can be challenging due to coupling interactions; also potential disturbances applied on one of the outputs may affect both. We therefore propose architectures for robustly manipulating the ratio/product and linear combinations of the outputs as well as each of the outputs independently. To demonstrate their characteristics, we apply these architectures to a simple process of two mutually activated biomolecular species. We also highlight the potential for experimental implementation by exploring synthetic realizations both in vivo and in vitro. This work presents an important step forward in building bio-devices capable of sophisticated functions.

Integration of Antimicrobials and Delivery Systems: Synergistic Antibiofilm Activity with Biodegradable Nanoemulsions Incorporating Pseudopyronine Analogs.

Multi-drug-resistant (MDR) bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), pose a significant challenge in healthcare settings. Small molecule antimicrobials (SMAs) such as α-pyrones have shown promise as alternative treatments for MDR infections. However, the hydrophobic nature of many SMAs limits their solubility and efficacy in complex biological environments. In this study, we encapsulated pseudopyronine analogs (PAs) in biodegradable polymer nanoemulsions (BNEs) for efficient eradication of biofilms. We evaluated a series of PAs with varied alkyl chain lengths and examined their antimicrobial activity against Gram-positive pathogens (S. aureus, MRSA, and B. subtilis). The selected PA with the most potent antibiofilm activity was incorporated into BNEs for enhanced solubility and penetration into the EPS matrix (PA-BNEs). The antimicrobial efficacy of PA-BNEs was assessed against biofilms of Gram-positive strains. The BNEs facilitated the solubilization and effective delivery of the PA deep into the biofilm matrix, addressing the limitations of hydrophobic SMAs. Our findings demonstrated that the PA2 exhibited synergistic antibiofilm activity when it was loaded into nanoemulsions. This study presents a promising platform for addressing MDR infections by combining pseudopyronine analogs with antimicrobial biodegradable nanoemulsions, overcoming challenges associated with treating biofilm infections.

Nacre‐Inspired Metal‐Organic Framework Coatings Reinforced by Multiscale Hierarchical Cross‐linking for Integrated Antifouling and Anti‐Microbial Corrosion

AbstractA long‐standing quest in marine materials science has been the development of tough and effective antifouling coatings for diverse surface protection. However, most commercial coatings are severely limited by poor mechanical behavior and unsustainable passive biocidal effect, leading to irreversible marine biofouling and even microbiologically influenced corrosion (MIC). Herein, inspired by the amorphous/crystalline feature within nacreous platelets, a mechanically robust antifouling coating composed of biopolymer‐based hydrogel and dense metal‐organic frameworks (MOFs) is developed. Tailoring the cross‐linked networks across multiscale interfaces can furnish strength, dissipate strain, and improve toughness of the building blocks, resulting in a firm and scalable configuration on various substrates regardless of material category and surface topology. The resultant coating as a suitable reservoir exhibits a unique active defensive behavior of intelligent MOF degradation or drug release, enabling a groundbreaking performance for broad‐spectrum biofouling and corrosion control. Notably, neither attachment of marine organisms nor MIC of metal substrates is observed and aggravated during the prolonged testing process in complex biological environments. This study provides distinctive insights into the underlying multimechanisms of comprehensive anti‐fouling‐corrosion and pioneer a rational strategy to design next‐generation reliable MOFs‐derived coatings in marine environments.