Interactions Of Biomolecules Research Articles

A Set of Three GdIII Spin Labels with Methanethiosulfonyl Groups for Bioconjugation Covering a Wide Range of EPR Line Widths.

Spin labels based on GdIII complexes are important tools for the elucidation of the structure, dynamics and interaction of biomolecules by electron paramagnetic resonance (EPR) spectroscopy. Their EPR spectroscopic properties line width and relaxation times influence their performance in a particular application. To be able to apply a complex well-suited for a specific application, a set of GdIII complexes with different EPR spectroscopic properties ready-made for spin labeling will be highly useful. We prepared three GdIII complexes with DO3APic, NO3Pic, and PyMTA as the basic ligand units. They cover a wide range of EPR line widths but have in common a cysteine-targeting methanethiosulfonyl (MTS) group connected to a pyridine ring, which is an intrinsic part of the ligand. The reaction with a cysteine-containing pentapeptide (0.45 mM in the peptide, pH ∼ 7) was complete within 90 s and chemoselective. The MTS group hydrolyzed with half-lives of >24, 8, 2, and 1 h at pH 5, 6, 7, and 8, respectively. The structurally related nicotinic acid-substituted disulfide (NDS) group was found to be hydrolytically much more stable. However, the MTS spin label clearly won the competition for the pentapeptide over the NDS spin label. If high reactivity is essential, MTS is clearly the better choice.

RuIII-Morpholine-Derived Thiosemicarbazone-Based Metallodrugs: Lysosome-Targeted Anticancer Agents.

The idea of coordinating biologically active ligand systems to metal centers to exploit their synergistic effects has gained momentum. Therefore, in this report, three RuIII complexes 1-3 of morpholine-derived thiosemicarbazone ligands have been prepared and characterized by spectroscopy and HRMS along with the structure of 2 through a single-crystal X-ray diffraction study. The solution stability of 1-3 was tested using conventional techniques such as UV-vis and HRMS. Further, the anticancer activity of 1-3 was tested in HT-29 and HeLa cancer cell lines. To gain insight into their mechanism of action, the cytotoxicity, hydrophobicity, and the interaction of 1-3 with DNA and HSA were evaluated by different conventional methods such as absorption, fluorescence, and circular dichroism studies. Along with favorable biomolecule interaction, 1-3 revealed potent selectivity toward cancer cells, which is a prerequisite for the generation of an anticancer drug. According to cell viability results, 1 has the highest cytotoxicity among all in the group, against both cells, respectively. Additionally, the fluorescence-active ruthenium complexes selectively target lysosomes, which is evaluated by live-cell imaging. 1-3 disrupt the lysosome membrane potential by generating an excessive amount of reactive oxygen species, which results in an apoptotic mode of cell death.

Analytical Techniques for Characterizing the Composition and Structure of Complex Biomolecules

The study explores analyzing complex biomolecules is essential for advancing our understanding of biological systems and their role in health and disease. This abstract provides an overview of analytical techniques used to characterize the composition and structure of these intricate biomolecules. One crucial technique is mass spectrometry, which enables the precise determination of a biomolecule's molecular weight and the identification of its constituent atoms and functional groups. Liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (MS/MS) are commonly employed for this purpose. These methods are particularly useful for analyzing proteins, nucleic acids, lipids, and carbohydrates. Nuclear magnetic resonance (NMR) spectroscopy is another indispensable tool for characterizing biomolecular structures. It provides atomic-level insights into three-dimensional structures, dynamics, and interactions. By measuring chemical shifts and coupling constants, NMR allows researchers to deduce the connectivity and conformation of complex biomolecules. X-ray crystallography, although mainly applied to proteins and larger biomolecules, provides high-resolution structural information. It involves the formation of crystalline structures that diffract X-rays, yielding detailed atomic structures. Electron microscopy, including cry-electron microscopy (cry-EM), is pivotal for visualizing macromolecular complexes and subcellular structures. It offers structural information at nanometre to near-atomic resolution, enabling the study of protein-protein interactions and organelle architecture. Infrared spectroscopy (IR) and circular dichroism (CD) spectroscopy are employed to probe biomolecule secondary structures, such as alpha-helices and beta-sheets, based on their unique vibrational and optical properties. These analytical techniques, when used in combination, provide a comprehensive view of the composition, conformation, and interactions of complex biomolecules. Their integration advances our understanding of fundamental biological processes and facilitates drug discovery and the development of therapeutic interventions.

Super-Resolved Protein Imaging Using Bifunctional Light-Up Aptamers.

Efficient labeling methods for protein visualization with minimal tag size and appropriate photophysical properties are required for single-molecule localization microscopy (SMLM), providing insights into the organization and interactions of biomolecules in cells at the molecular level. Among the fluorescent light-up aptamers (FLAPs) originally developed for RNA imaging, RhoBAST stands out due to its remarkable brightness, photostability, fluorogenicity, and rapid exchange kinetics, enabling super-resolved imaging with high localization precision. Here, we expand the applicability of RhoBAST to protein imaging by fusing it to protein-binding aptamers. The versatility of such bifunctional aptamers is demonstrated by employing a variety of protein-binding aptamers and different FLAPs. Moreover, fusing RhoBAST with the GFP-binding aptamer AP3 facilitates high- and super-resolution imaging of GFP-tagged proteins, which is particularly valuable in view of the widespread availability of plasmids and stable cell lines expressing proteins fused to GFP. The bifunctional aptamers compare favorably with standard antibody-based immunofluorescence protocols, as they are 7-fold smaller than antibody conjugates and exhibit higher bleaching-resistance. We demonstrate the effectiveness of our approach in super-resolution microscopy in secondary mammalian cell lines and primary neurons by RhoBAST-PAINT, an SMLM protein imaging technique that leverages the transient binding of the fluorogenic rhodamine dye SpyRho to RhoBAST.

Pathways in Biomimicry to Enhance Solar Technology Capabilities

Efficiency, longevity, and cost-effectiveness in current solar modules are compromised in pursuit of best balancing one another. This report explores the potential of enhancing solar cell practicability through biomimicry. Like solar cells, biological organisms absorb heat during photosynthesis, positioning nature as an inherent source of inspiration to tackle current technological challenges. Significant improvements have been achieved by mimicking structures such as the leaf epidermis for multidirectional light capture, cell membranes for protective encapsulation, and butterfly wings for enhanced light absorption and reflection. For instance, incorporating a BT layer for thermoregulation mimics plant transpiration, enhancing cooling efficiency. Additionally, hierarchical structures inspired by leaf geometry increases angular robustness in both dye-sensitized solar cells and passive emitter and rear cells, and lipid biomolecule interactions shelter halide perovskites from environmental degradation. The nanostructures of butterfly wings also show promise in supporting thin film PVs to overcome conversion inefficiency. Lastly, the reflective properties of butterfly wings have led to advancements in solar concentrators, improving power-to-weight ratios. These examples highlight the untapped potential of biomimicry in furthering the viability and deployment of solar technologies.

Effect and mechanism of different exogenous biomolecules on the thermal-induced gel properties of surimi: A review.

Surimi products are favored by domestic and foreign consumers due to their distinctive gelatinous texture, rich nutrition, and convenient consumption. Gel properties are key evaluation indicators for the quality of surimi products, which was mainly determined by the gel-forming ability of the myofibrillar protein (MP). In recent years, the surimi processing industry has faced challenges in product quality that limits the further development, and how to effectively improve the gel properties of surimi products has become one of the key scientific problems to be solved in surimi processing industry. A viable strategy for improving the product quality involves combining surimi with exogenous additives, such as proteins, polysaccharides, and lipids, to enhance the gel-forming ability of MP. At present, there is limited literature review to systematically investigate the role of these exogenous additives in interacting with MPs in surimi gel system and their effect on the gel properties of heat-induced surimi. Therefore, in this review, we systematically discussed the formation mechanism and influencing factors of surimi gel, the interactions of exogenous biomolecules (proteins, polysaccharides, and lipids) with surimi protein, as well as their effects on the gel properties of surimi product. The aim of this review was to help us with a better understanding for the intrinsic action mechanisms of complex surimi system and provide some theoretical guidance for the improvement of gel quality and development of surimi products.

Circ2DGNN: circRNA-disease Association Prediction via Transformer-based Graph Neural Network.

Investigating the associations between circRNA and diseases is vital for comprehending the underlying mechanisms of diseases and formulating effective therapies. Computational prediction methods often rely solely on known circRNA-disease data, indirectly incorporating other biomolecules' effects by computing circRNA and disease similarities based on these molecules. However, this approach is limited, as other biomolecules also play significant roles in circRNA-disease interactions. To address this, we construct a comprehensive heterogeneous network incorporating data on human circRNAs, diseases, and other biomolecule interactions to develop a novel computational model, circ2DGNN, which is built upon a heterogeneous graph neural network. circ2DGNN directly takes heterogeneous networks as inputs and obtains the embedded representation of each node for downstream link prediction through graph representation learning. circ2DGNN employs a Transformer-like architecture, which can compute heterogeneous attention score for each edge, and perform message propagation and aggregation, using a residual connection to enhance the representation vector. It uniquely applies the same parameter matrix only to identical meta-relationships, reflecting diverse parameter spaces for different relationship types. After fine-tuning hyperparameters via five-fold cross-validation, evaluation conducted on a test dataset shows circ2DGNN outperforms existing state-of-the-art(SOTA) methods.

Super‐Resolved Protein Imaging Using Bifunctional Light‐Up Aptamers

AbstractEfficient labeling methods for protein visualization with minimal tag size and appropriate photophysical properties are required for single‐molecule localization microscopy (SMLM), providing insights into the organization and interactions of biomolecules in cells at the molecular level. Among the fluorescent light‐up aptamers (FLAPs) originally developed for RNA imaging, RhoBAST stands out due to its remarkable brightness, photostability, fluorogenicity, and rapid exchange kinetics, enabling super‐resolved imaging with high localization precision. Here, we expand the applicability of RhoBAST to protein imaging by fusing it to protein‐binding aptamers. The versatility of such bifunctional aptamers is demonstrated by employing a variety of protein‐binding aptamers and different FLAPs. Moreover, fusing RhoBAST with the GFP‐binding aptamer AP3 facilitates high‐ and super‐resolution imaging of GFP‐tagged proteins, which is particularly valuable in view of the widespread availability of plasmids and stable cell lines expressing proteins fused to GFP. The bifunctional aptamers compare favorably with standard antibody‐based immunofluorescence protocols, as they are 7‐fold smaller than antibody conjugates and exhibit higher bleaching‐resistance. We demonstrate the effectiveness of our approach in super‐resolution microscopy in secondary mammalian cell lines and primary neurons by RhoBAST‐PAINT, an SMLM protein imaging technique that leverages the transient binding of the fluorogenic rhodamine dye SpyRho to RhoBAST.

Initiation of Medial Calcification: Revisiting Calcium Ion Binding to Elastin.

Pathological calcification of elastin, a key connective tissue protein in the medial layers of blood vessels, starts with the binding of calcium ions. This Mini-Review focuses on understanding how calcium ions interact with elastin to initiate calcification at a molecular level, and emphasizes water's critical role in mediating this interaction. In the past decade, great strides have been made in understanding and modeling ion-specific hydration and its effects on biomolecule interactions. However, these advances have been largely absent from our understanding of elastin calcification. Historically, charge-neutral backbone carbonyls and negatively charged carboxyl groups have been proposed as elastin's calcium binding sites. Recently, tropoelastin's only four carboxyl groups have been identified as binding sites from classical molecular dynamics (MD). While carboxyl groups have a much higher affinity for binding calcium ions than backbone carbonyls, conflicting evidence persists for both functional group's importance in elastin calcification. This can be attributed to the fact that divalent ions strongly polarize water, leading to a hydration shell that shields electrostatic forces. The hydration shell surrounding both a calcium ion and either of the proposed binding sites must be displaced to enable binding. Providing our own extended X-ray absorption fine structure (EXAFS) data and complementary simulations, we discuss the potential structures of calcium binding in elastin and review prior knowledge regarding the relative importance of the two proposed binding sites.

Tailoring copolymer architectures and macromolecular interactions for enhanced nanotherapeutic delivery: A design-by-architecture approach

Amphiphilic copolymers with precise macromolecular topologies are crucial in nanomedicine for enhancing drug delivery by improving solubilization, stabilization, and therapeutic efficacy on target tissues. This study employs a design-by-architecture approach to identify factors influencing interactions between synthesized macromolecules and biological systems for optimal drug nanodelivery. Copolymers combining poly(ε-caprolactone) blocks and poly(polyethylene glycol methacrylate) or poly(glycerol methacrylate), were synthesized to investigate how architectural adjustments impact self-assembly, nanoparticle size, drug loading, and biomolecule interactions. Linear and brush block copolymers with varied block lengths were studied for their self-assembly behavior in aqueous environments. Both copolymer types formed smaller nanoparticles with extended hydrophilic blocks, with brush block copolymers showing superior performance due to their peculiar macromolecular architecture. Incorporating ‘clickable’ glycidyl units within the hydrophilic block minimally affected particle size. Controlled functionalization with thiol groups resulted in stable nanoparticles with enhanced size reduction and mucoadhesive properties, potentially improving targeted drug delivery and therapeutic effects.

Cathodoluminescent and Characteristic X-Ray-Emissive Rare-Earth-Doped Core/Shell Protein Labels for Spectromicroscopic Analysis of Cell Surface Receptors.

Understanding the localization and the interactions of biomolecules at the nanoscale and in the cellular context remains challenging. Electron microscopy (EM), unlike light-based microscopy, gives access to the cellular ultrastructure yet results in grey-scale images and averts unambiguous (co-)localization of biomolecules. Multimodal nanoparticle-based protein labels for correlative cathodoluminescence electron microscopy (CCLEM) and energy-dispersive X-ray spectromicroscopy (EDX-SM) are presented. The single-particle STEM-cathodoluminescence (CL) and characteristic X-ray emissivity of sub-20 nm lanthanide-doped nanoparticles are exploited as unique spectral fingerprints for precise label localization and identification. To maximize the nanoparticle brightness, lanthanides are incorporated in a low-phonon host lattice and separated from the environment using a passivating shell. The core/shell nanoparticles are then functionalized with either folic (terbium-doped) or caffeic acid (europium-doped). Their potential for (protein-)labeling is successfully demonstrated using HeLa cells expressing different surface receptors that bind to folic or caffeic acid, respectively. Both particle populations show single-particle CL emission along with a distinctive energy-dispersive X-ray signal, with the latter enabling color-based localization of receptors within swift imaging times well below 2 min per 2 while offering high resolution with a pixel size of 2.78 nm. Taken together, these results open a route to multi-color labeling based on electronspectromicroscopy.

The Current Status and Future Directions on Nanoparticles for Tumor Molecular Imaging.

Molecular imaging is an advanced technology that utilizes specific probes or markers in conjunction with cutting-edge imaging techniques to observe and analyze the localization, distribution, activity, and interactions of biomolecules within living organisms. Tumor molecular imaging, by enabling the visualization and quantification of molecular characteristics of tumor cells, facilitates a deeper and more comprehensive understanding of tumors, providing valuable insights for early diagnosis, treatment monitoring, and cancer biology research. However, the image quality of molecular imaging still requires improvement, and nanotechnology has significantly propelled the advancement of molecular imaging. Currently, nanoparticle-based tumor molecular imaging technologies encompass radionuclide imaging, fluorescence imaging, magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, and multimodal imaging, among others. As our understanding of the tumor microenvironment deepens, the design of nanoparticle probes for tumor molecular imaging has also evolved, offering new perspectives and expanding the applications of tumor molecular imaging. Beyond diagnostics, there is a marked trend towards integrated diagnosis and therapy, with image-guided treatment playing a pivotal role. This includes image-guided surgery, photodynamic therapy, and chemodynamic therapy. Despite continuous advancements and innovative developments in molecular imaging, many of these remain in the experimental stage and require breakthroughs before they can be fully integrated into clinical practice.

A Linkable, Polycarbonate Gut Microbiome-Distal Tumor Chip Platform for Interrogating Cancer Promoting Mechanisms.

Gut microbiome composition is tied to diseases ranging from arthritis to cancer to depression. However, mechanisms of action are poorly understood, limiting development of relevant therapeutics. Organ-on-chip platforms, which model minimal functional units of tissues and can tightly control communication between them, are ideal platforms to study these relationships. Many gut microbiome models are published to date but devices are typically fabricated using oxygen permeable polydimethylsiloxane, requiring interventions to support anaerobic bacteria. To address this challenge, a platform is developed where the chips are fabricated entirely from gas-impermeable polycarbonate without tapes or gaskets. These chips replicate polarized villus-like structures of the native tissue. Further, they enable co-cultures of commensal anaerobic bacteria Blautia coccoides on the surface of gut epithelia for two days within a standard incubator. Another complication of commonly used materials in organ-on-chip devices is high ad-/absorption, limiting applications in high-resolution microscopy and biomolecule interaction studies. For future communication studies between gut microbiota and distal tumors, an additional polycarbonate chip design is developed to support hydrogel-embedded tissue culture. These chips enable high-resolution microscopy with all relevant processing done on-chip. Designed for facile linking, this platform will make a variety of mechanistic studies possible.

Interaction of Purine and its Derivatives with A1, A2-Adenosine Receptors and Vascular Endothelial Growth Factor Receptor-1 (Vegf-R1) as a Therapeutic Alternative to Treat Cancer.

There are several studies that indicate that cancer development may be conditioned by the activation of some biological systems that involve the interaction of different biomolecules, such as adenosine and vascular endothelial growth factor. These biomolecules have been targeted of some drugs for treat of cancer; however, there is little information on the interaction of purine derivatives with adenosine and vascular endothelial growth factor receptor (VEGF-R1). The aim of this research was to determine the possible interaction of purine (1: ) and their derivatives (2-31: ) with A1, A2-adenosine receptors, and VEGF-R1. Theoretical interaction of purine and their derivatives with A1, A2-adenosine receptors and VEGF-R1 was carried out using the 5uen, 5mzj and 3hng proteins as theoretical tools. Besides, adenosine, cgs-15943, rolofylline, cvt-124, wrc-0571, luf-5834, cvt-6883, AZD-4635, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls. The results showed differences in the number of aminoacid residues involved in the interaction of purine and their derivatives with 5uen, 5mzj and 3hng proteins compared with the controls. Besides, the inhibition constants (Ki) values for purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: were lower compared with the controls CONCLUSIONS: Theoretical data suggest that purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: could produce changes in cancer cell growth through inhibition of A1, A2-adenosine receptors and VEGFR-1 inhibition. These data indicate that these purine derivatives could be a therapeutic alternative to treat some types of cancer.

DNA Aptamer Integrated Hydrogel Nanocomposites on Screen Printed Gold Electrodes for Point-of-Care Detection of Testosterone in Human Serum.

This work describes the development and evaluation of a novel electrochemical aptasensor for testosterone detection. The sensor utilizes a specifically designed DNA immobilized on a screen-printed gold electrode (SPGE) modified with a conductive hydrogel and gold nanoparticles (HG/NP) composite. The aptasensor exhibited a dose-dependent response to testosterone (0.05 to 50 ng/mL) with a detection limit of 0.14 ng/mL and a good sensitivity of 0.23 μA ng-1 mL cm-2. The sensor displayed excellent selectivity towards testosterone compared to structurally similar steroid hormones. Importantly, the incorporation of HG/NP not only improved the sensor's conductivity but also acted as an antifouling layer, minimizing signal interference from non-specific biomolecule interactions in complex biological samples like human serum. The results obtained from the aptasensor showed good correlation with a standard ELISA method, demonstrating its effectiveness in real-world scenarios.

Quantifying biomolecular organisation in membranes with brightness-transit statistics

Cells crucially rely on the interactions of biomolecules at their plasma membrane to maintain homeostasis. Yet, a methodology to systematically quantify biomolecular organisation, measuring diffusion dynamics and oligomerisation, represents an unmet need. Here, we introduce the brightness-transit statistics (BTS) method based on fluorescence fluctuation spectroscopy and combine information from brightness and transit times to elucidate biomolecular diffusion and oligomerisation in both cell-free in vitro and in vitro systems incorporating living cells. We validate our approach in silico with computer simulations and experimentally using oligomerisation of EGFP tethered to supported lipid bilayers. We apply our pipeline to study the oligomerisation of CD40 ectodomain in vitro and endogenous CD40 on primary B cells. While we find a potential for CD40 to oligomerize in a concentration or ligand depended manner, we do not observe mobile oligomers on B cells. The BTS method combines sensitive analysis, quantification, and intuitive visualisation of dynamic biomolecular organisation.

Interactions of coinage metal nanoclusters with low-molecular-weight biocompounds.

Nowadays, coinage metal nanoclusters (NCs) are largely presented in diagnostics, bioimaging, and biocatalysis due to their high biocompatibility, chemical stability, and sensitivity to surrounding biomolecules. Silver and gold NCs are usually characterized by intense luminescence and photostability, which is in great demand in the detection of organic compounds, ions, pH, temperature, etc. The experimental synthesis of metal NCs often occurs on biopolymer templates, mostly DNA and proteins. However, this review mainly focuses on the interactions with small biomolecules (SBMs) of a molecular weight less than 1000 Da: amino acids, nucleobases, thiolates, oligopeptides, etc. Such molecules can serve as the templates for an eco-friendly facile one-pot synthesis of biocompatible luminescent NCs. The latter aspect makes NCs suitable for diagnostics and intracellular bioimaging. Another important aspect is the interaction of clusters with biomarkers, which is largely exploited by nanosensors: biomarker detection often occurs through either fluorescence emission "turn-on" or "turn-off" mechanisms. Moreover, as theoretical studies show, electronic absorption spectra and Raman spectra of the metal-organic complexes allow efficient detection of various analytes. In this regard, both theoretical and experimental studies of SBM complexes with metal NCs are in great demand. Therefore, this review aims to summarize up-to-date studies on the interaction of small biomolecules with coinage metal NCs from both theoretical and experimental viewpoints.

Expanding the Role of Chiral Drugs and Chiral Nanomaterials as a Potential Therapeutic Tool.

Chirality, the property of molecules having mirror-image forms, plays a crucial role in pharmaceutical and biomedical research. This review highlights its growing importance, emphasizing how chiral drugs and nanomaterials impact drug effectiveness, safety, and diagnostics. Chiral molecules serve as precise diagnostic tools, aiding in accurate disease detection through unique biomolecule interactions. The article extensively covers chiral drug applications in treating cardiovascular diseases, CNS disorders, local anesthesia, anti-inflammatories, antimicrobials, and anticancer drugs. Additionally, it explores the emerging field of chiral nanomaterials, highlighting their suitability for biomedical applications in diagnostics and therapeutics, enhancing medical treatments.

An Amphiphilic Cell-Penetrating Macrocycle for Efficient Cytosolic Delivery of Proteins, DNA, and CRISPR Cas9.

The discovery of safe platforms that can circumvent the endocytic pathway is of great significance for biological therapeutics that are usually degraded during endocytosis. Here we show that a self-assembled and dynamic macrocycle can passively diffuse through the cell membrane and deliver a broad range of biologics, including proteins, CRISPR Cas9, and ssDNA, directly to the cytosol while retaining their bioactivity. Cell-penetrating macrocycle CPM can be easily prepared from the room temperature condensation of diketopyrrolopyrrole lactams with diamines. We attribute the high cellular permeability of CPM to its amphiphilic nature and chameleonic properties. It adopts conformations that partially bury polar groups and expose hydrophobic side chains, thus self-assembling into micellar-like structures. Its superior fluorescence makes CPM trackable inside cells where it follows the endomembrane system. CPM outperformed commercial reagents for biologics delivery and showed high RNA knockdown efficiency of CRISPR Cas9. We envisage that this macrocycle will be an ideal starting point to design and synthesize biomimetic macrocyclic tags that can readily facilitate the interaction and uptake of biomolecules and overcome endosomal digestion.

An Amphiphilic Cell‐Penetrating Macrocycle for Efficient Cytosolic Delivery of Proteins, DNA, and CRISPR Cas9

AbstractThe discovery of safe platforms that can circumvent the endocytic pathway is of great significance for biological therapeutics that are usually degraded during endocytosis. Here we show that a self‐assembled and dynamic macrocycle can passively diffuse through the cell membrane and deliver a broad range of biologics, including proteins, CRISPR Cas9, and ssDNA, directly to the cytosol while retaining their bioactivity. Cell‐penetrating macrocycle CPM can be easily prepared from the room temperature condensation of diketopyrrolopyrrole lactams with diamines. We attribute the high cellular permeability of CPM to its amphiphilic nature and chameleonic properties. It adopts conformations that partially bury polar groups and expose hydrophobic side chains, thus self‐assembling into micellar‐like structures. Its superior fluorescence makes CPM trackable inside cells where it follows the endomembrane system. CPM outperformed commercial reagents for biologics delivery and showed high RNA knockdown efficiency of CRISPR Cas9. We envisage that this macrocycle will be an ideal starting point to design and synthesize biomimetic macrocyclic tags that can readily facilitate the interaction and uptake of biomolecules and overcome endosomal digestion.