Reversible Interactions Research Articles

New electrophiles targeting thiols in a reversible covalent manner.

Reversible covalent electrophiles with the advantages of both reversible and covalent interactions receive much attention in the fields of chemical biology and medicinal chemistry. Here, we report two electron-deficient olefins activated by amide and ester, amide-substituted acrylamide and methyl ester-substituted acrylamide, targeting thiols in a reversible covalent manner.

Exploring the time-dependent and wavelength-guided tunable binary and ternary logic behaviours of a charge-transfer probe.

This study presents the development of a novel time-dependent logic behaviour system and a state-of-the-art inter-switchable ternary molecular logic system, comprising 3-input INHIBIT and 3-input TRANSFER logic gates driven by elementary chemical interactions. The absorption spectra of the probe molecule underwent versatile time-dependent changes upon the individual and simultaneous addition of two analytes, namely F- and CN-, leading to alterations in the logic behaviour observed at both the 295 nm (from AND to TRANSFER) and 400 nm bands (from OR to INHIBIT). Additionally, we explored the creation of wavelength-guided molecular logic systems that leverage reversible (F- and H2O) and irreversible (CN- and H2O) chemical interactions. By employing CN- and H2O as dual chemical inputs, we derived binary TRANSFER, 2-input PASS 0, and binary COMPLEMENT logic gates based on the opto-chemical responses at 295 nm, 400 nm, and 500 nm, respectively. Lastly, we introduced an innovative inter-switchable ternary molecular logic system, involving 3-input INHIBIT and 3-input TRANSFER logic gates, using F-, CN-, and H2O as ternary chemical inputs, capitalizing on the probes' versatile and distinct absorption responses at varying wavelengths (400 and 295 nm, respectively).

High adsorption of ammonia in a titanium-based metal-organic framework.

We report the high adsorption of NH3 in a titanium-based metal-organic framework, MFM-300(Ti), comprising extended [TiO6]∞ chains linked by biphenyl-3,3',5,5'-tetracarboxylate ligands. At 273 K and 1 bar, MFM-300(Ti) shows an exceptional NH3 uptake of 23.4 mmol g-1 with a record-high packing density of 0.84 g cm-3. Dynamic breakthrough experiments confirm the excellent uptake and separation of NH3 at low concentration (1000 ppm). The combination of in situ neutron powder diffraction and spectroscopic studies reveal strong, yet reversible binding interactions of NH3 to the framework oxygen sites.

Tough, self-healing and injectable dynamic nanocomposite hydrogel based on gelatin and sodium alginate

Biomacromolecules based injectable and self-healing hydrogels possessing high mechanical properties have widespread potential in biomedical field. However, dynamic features are usually inversely proportional to toughness. It is challenging to simultaneously endow these properties to the dynamic hydrogels. Here, we fabricated an injectable nanocomposite hydrogel (CS-NPs@OSA-l-Gtn) stimultaneously possessing excellent autonomous self-healing performance and high mechanical strength by doping chitosan nanoparticles (CS-NPs) into dynamic polymer networks of oxidized sodium alginate (OSA) and gelatin (Gtn) in the presence of borax. The synergistic effect of the multiple reversible interactions combining dynamic covalent bonds (i.e., imine bond and borate ester bond) and noncovalent interactions (i.e., electrostatic interaction and hydrogen bond) provide effective energy dissipation to endure high fatigue resistance and cyclic loading. The dynamic hydrogel exhibited excellent mechanical properties like maximum 2.43 MPa compressive strength, 493.91 % fracture strain, and 89.54 kJ/m3 toughness. Moreover, the integrated hydrogel after injection and self-healing could withstand 150 successive compressive cycles. Besides, the bovine serum albumin embedded in CS-NPs could be sustainably released from the nanocomposite hydrogel for 12 days. This study proposes a novel strategy to synthesize an injectable and self-healing hydrogel combined with excellent mechanical properties for designing high-strength natural carriers with sustained protein delivery.

Responsive pillar[n]arene materials

AbstractIntelligent materials with responsive behaviors toward external stimuli, such as light, temperature, pH, redox, and solvent have been increasingly fascinating. Reversible noncovalent interactions provide an efficient way to construct stimuli‐responsive materials. Macrocyclic compounds, such as cyclodextrins, cucurbit[n]urils, calix[n]arenes, crown ethers, and related macrocycles, are useful skeletons for constructing such materials through host–guest interactions. Pillar[n]arenes are pillar‐shaped macrocyclic hosts developed by our groups in 2008, in which the repeated 1,4‐dialkoxybenzene units are connected by methylene bridges at the para position. The versatile functionality, easy modification, excellent size‐dependent host–guest complexation, and adjustable electron density of the cavity endow pillar[n]arenes with excellent properties compared with other cyclic host molecules. Moreover, the unique planar chirality and chirality inversion generated by unit rotation make pillar[n]arenes ideal platforms for investigating chirality inversion, induction, and transformation. In this review, we describe stimuli‐responsive topological, optical, chiroptical, supramolecular assemblies, and solid‐state materials based on the host–guest complexation and structural regulation of pillar[n]arenes.

Dynamic conformational changes of a tardigrade group-3 late embryogenesis abundant protein modulate membrane biophysical properties.

A number of intrinsically disordered proteins (IDPs) encoded in stress-tolerant organisms, such as tardigrade, can confer fitness advantage and abiotic stress tolerance when heterologously expressed. Tardigrade-specific disordered proteins including the cytosolic-abundant heat-soluble proteins are proposed to confer stress tolerance through vitrification or gelation, whereas evolutionarily conserved IDPs in tardigrades may contribute to stress tolerance through other biophysical mechanisms. In this study, we characterized the mechanism of action of an evolutionarily conserved, tardigrade IDP, HeLEA1, which belongs to the group-3 late embryogenesis abundant (LEA) protein family. HeLEA1 homologs are found across different kingdoms of life. HeLEA1 is intrinsically disordered in solution but shows a propensity for helical structure across its entire sequence. HeLEA1 interacts with negatively charged membranes via dynamic disorder-to-helical transition, mainly driven by electrostatic interactions. Membrane interaction of HeLEA1 is shown to ameliorate excess surface tension and lipid packing defects. HeLEA1 localizes to the mitochondrial matrix when expressed in yeast and interacts with model membranes mimicking inner mitochondrial membrane. Yeast expressing HeLEA1 shows enhanced tolerance to hyperosmotic stress under nonfermentative growth and increased mitochondrial membrane potential. Evolutionary analysis suggests that although HeLEA1 homologs have diverged their sequences to localize to different subcellular organelles, all homologs maintain a weak hydrophobic moment that is characteristic of weak and reversible membrane interaction. We suggest that such dynamic and weak protein-membrane interaction buffering alterations in lipid packing could be a conserved strategy for regulating membrane properties and represent a general biophysical solution for stress tolerance across the domains of life.

Highly Adhesive and Self-Healing Zwitterionic Hydrogels as Antibacterial Coatings for Medical Devices.

Bacterial infection of medical devices has caused incalculable losses to maintenance costs and health care. A single coating with antibacterial function cannot guarantee the long-term use of the device, because the coating will be damaged and fall off during reuse. To solve this problem, the development of coatings with high adhesion and self-healing ability is a wise direction. In this paper, a multifunctional polyzwitterionic antibacterial hydrogel coating (PZG) composed of amphozwitterion monomer, anionic monomer, and quaternary ammonium cationic monomer was synthesized by dipping UV photoinitiated polymerization. The structure of PZGs was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Ascribing to the hydrogel internal electrostatic interaction, hydrogen bond, and cation-π interaction, the obtained PZGs exhibited high ductility (>1200% strain) and appropriate strength (>189 kPa). Remarkably, PZGs could also adhere firmly on different substrates through noncovalent interaction, and their adhesion could be controlled by adjusting the amount of zwitterionic. Reversible physical interactions in polymer networks endowed hydrogels with excellent self-healing properties. In addition, PZGs exhibit good antibacterial activity and biocompatibility due to the synergistic effect of quaternary ammonium cation and amphozwitterion monomer. This work provides a multifunctional antibacterial coating for medical equipment and has broad application prospects in the biomedical field.

Probing the Molecular Mechanism of Viscoelastic Relaxation in Transient Networks.

Hydrogels, which have polymer networks through supramolecular and reversible interactions, exhibit various mechanical responsibilities to its surroundings. The influence of the reversible bonds on a hydrogel's macroscopic properties, such as viscoelasticity and dynamics, is not fully understood, preventing further innovative material development. To understand the relationships between the mechanical properties and molecular structures, it is required to clarify the molecular understanding of the networks solely crosslinked by reversible interactions, termed "transient networks". This review introduces our recent progress on the studies on the molecular mechanism of viscoelasticity in transient networks using multiple methods and model materials. Based on the combination of the viscoelasticity and diffusion measurements, the viscoelastic relaxation of transient networks does not undergo the diffusion of polymers, which is not explained by the framework of conventional molecular models for the viscoelasticity of polymers. Then, we show the results of the comparison between the viscoelastic relaxation and binding dynamics of reversible bonds. Viscoelastic relaxation is primarily affected by "dissociation dynamics of the bonds" and "network structures". These results are explained in the framework that the backbone, which is composed of essential chains supporting the stress, is broken by multiple dissociation events. This understanding of molecular dynamics in viscoelasticity will provide the foundation for designing transient networks.

Antibacterial hyaluronic acid hydrogels with enhanced self-healing properties via multiple dynamic bond crosslinking

The self-healing hydrogel offering intrinsic antibacterial activity is often required for the treatment of wounds because it can provide effective wound protection and prevent wound infection. Herein, antibacterial hyaluronic acid hydrogels with enhanced self-healing performances are prepared by multiple dynamic-bond crosslinking between aldehyde hyaluronic acid, 3, 3′- dithiobis (propionyl hydrazide) and fungal-sourced quaternized chitosan. Due to the formation of these different types of reversible interactions e.g. hydrazone bonds, disulfide bonds, and electrostatic interactions, the hyaluronic acid hydrogels can gel rapidly and exhibit excellent self-healing ability, which can heal completely within 1 h. Furthermore, the hydrogels show good antibacterial activity against E. coli and S. aureus with an inhibition ratio of ~100 % and above 75 %, respectively. Additionally, the hydrogels are cytocompatible, which makes them the potential for biomedical applications e.g. cell culture, tissue engineering, and wound dressing.

Robust conductive nanocomposite hydrogels with an interpenetrating network based on polyaniline for flexible supercapacitors

AbstractConductive polyacrylic acid/polyaniline/SiO2 (PAA/PANI/SiO2) nanocomposite hydrogels as electrolytes for a high‐performance flexible supercapacitor were prepared by combining in situ radical polymerization of anionic monomer acrylic acid, in situ sol–gel reaction of vinyltriethoxysilane (VTES), and oxidative polymerization of conductive monomer aniline (ANI). In the nanocomposite hydrogel, vinyl‐SiO2 nanoparticles served as analogous covalent crosslinkers, while the reversible noncovalent interactions (such as hydrogen bonds, electrostatic interactions, and chain entanglements) between the PAA/SiO2 and PANI networks acted as physical crosslinkers. The interconnected PANI and PAA/SiO2 networks thus constructed an interpenetrating three‐dimensional network that improved the movement of electrons and ions while also enhancing the mechanical properties of the hydrogel. At a volume ratio of ANI to VTES of 50:200, the compressive strength and conductivity of PAA/PANI/SiO2 hydrogels were as high as 1505 kPa and 4.42 S/m, respectively. Moreover, the flexible supercapacitors based on the nanocomposite hydrogel electrolyte exhibited high specific capacitance (574.7 F/g), energy density (19.6 Wh/kg), and power density (1.4 kW/kg) at a current density of 0.05 A/g. Meanwhile, these supercapacitors exhibit exceptional flexibility and mechanical stability, and can be repeatedly bent without degrading performance. This nanocomposite hydrogel has considerable potential for use in other flexible energy devices and electronics due to its excellent mechanical and electrochemical properties.Highlights Conductive nanocomposite hydrogel have good conductivity and mechanical properties. Conductive hydrogels are used as electrolytes for flexible supercapacitors. Vinyl‐SiO2 served as analogous covalent crosslinkers for the hydrogel. Noncovalent bonds between PAA/SiO2 and PANI acted as physical crosslinkers. Interconnected PANI and PAA/SiO2 networks formed an interpenetrating network.

Self-Healing Iron Oxide Polyelectrolyte Nanocomposites: Influence of Particle Agglomeration and Water on Mechanical Properties

Self-healing nanocomposites can be generated by organic functionalization of inorganic nanoparticles and complementary functionalization of the polymer matrix, allowing reversible interactions between the two components. Here, we report on self-healing nanocomposites based on ionic interactions between anionic copolymers consisting of di(ethylene glycol) methyl ether methacrylate, sodium 4-(methacryloyloxy)butan-1-sulfonate, and cationically functionalized iron oxide nanoparticles. The materials exhibited hygroscopic behavior. At water contents < 6%, the shear modulus was reduced by up to 90%. The nanoparticle concentration was identified as a second factor strongly influencing the mechanical properties of the materials. Backscattered scanning electron microscopy and small-angle X-ray scattering measurements showed the formation of agglomerates in the size range of 100 nm to a few µm in diameter, independent of concentration, resulting in the disordering of the semi-crystalline ionic polymer blocks. These effects resulted in an increase in the shear modulus of the composite from 3.7 MPa to 5.6 MPa, 6.3 Mpa, and 7.5 MPa for 2, 10, and 20 wt% particles, respectively. Temperature-induced self-healing was possible for all composites investigated. However, only 36% of the maximum stress could be recovered in systems with a low nanoparticle content, whereas the original properties were largely restored (>85%) at higher particle contents.

Synthetically encoded complementary oligomers.

Creating the next generation of advanced materials will require controlling molecular architecture to a degree typically achieved only in biopolymers. Sequence-defined polymers take inspiration from biology by using chain length and monomer sequence as handles for tuning structure and function. These sequence-defined polymers can assemble into discrete structures, such as molecular duplexes, via reversible interactions between functional groups. Selectivity can be attained by tuning the monomersequence, therebycreating the need for chemical platforms that can produce sequence-defined polymers at scale. Developing sequence-defined polymers that are specific for their complementary sequence and achieve their desired binding strengths is critical for producing increasingly complex structures for new functional materials. In this Review Article, we discuss synthetic platforms that produce sequence-defined, duplex-forming oligomers of varying length, strength and association mode, and highlight several analytical techniques usedto characterize their hybridization.

Healable Ionic Conductors with Extremely Low-Hysteresis and High Mechanical Strength Enabled by Hydrophobic Domain-Locked Reversible Interactions.

Extremely low hysteresis, high mechanical strength, superior toughness, and excellent healability are essential for stretchable ionic conductors to enhance their reliability and meet for cutting-edge applications. However, the fabrication of stretchable ionic conductors with such mutually exclusive properties remains challenging. Herein, extremely low-hysteresis and healable ionic conductors with a tensile strength of ≈8.9MPa and toughness of ≈23.2MJ m-3 are fabricated through the complexation of 4-carboxybenzaldehyde (CBA) grafted poly(vinyl alcohol) (PVA) (denoted as PVA-CBA) and poly (allylamine hydrochloride) (PAH) followed by acidification and ion-loading steps. The acidification step generates the PVA-CBA/PAH ionic conductors with in situ formed dynamic hydrophobic domains that lock and stabilize noncovalent interactions. This significantly minimizes the energy dissipation of the ionic conductors during cyclic mechanical loading (≤200% strain), resulting in ionic conductors with extremely low hysteresis (≈5%). The fractured ionic conductors can be healed at 60°C to restore their original properties. Because of the extremely low hysteresis, the PVA-CBA/PAH ionic conductors show a highly stable and reproducible electrical response over 5000 uninterrupted loading-unloading cycles at a strain of 200%. The ionic conductor based sensors exhibit a high sensitivity to a wide range of strains (1-500%).

A systematic investigation of Pr-rich Pr-(Fe,Co)-B material system: Phase formation, microstructure and magnetic property

Praseodymium (Pr) doping is known to increase the coercivity of Nd-Fe-B permanent magnets without significant reduction in magnetization. However, there is still a lack of studies on the specific impact of Pr in comparison of Nd on phase formation and microstructure, which is crucial for the development of high-performance Pr-based magnets. In this study, we investigate the phase formation, microstructure, magnetic properties and coercivity mechanisms in Pr-rich Pr15(Fe1-xCox)78B7 (x = 0 – 1) alloys using advanced synthesis, high-resolution electron microscopy, and modeling techniques. The alloys with x = 0 and 0.2 are comprised of a Pr2(Fe,Co)14B matrix phase with a non-magnetic Pr-rich intergranular phase, and this microstructure is stable up to 1150 °C. Due to the Pr-rich phase, the magnetization reversal in Pr2(Fe,Co)14B grains is hindered, resulting in high coercivity of 1.8 ∼ 2.0 T. For the Co concentration of x = 0.4 - 0.8, the Pr-rich intergranular phase gradually disappears, and ferromagnetic Pr(Fe,Co)4B, Pr(Fe,Co)2 or Pr(Fe,Co)3 phases are exist instead. The soft-magnetic Pr(Fe,Co)2 phase acts as a weak link and tends to induce the nucleation of the reversal interaction domain inside the Pr2(Fe,Co)14B grain near the Pr(Fe,Co)2 / Pr2(Fe,Co)14B interface, resulting in degraded coercivity of 0.7 ∼ 1.0 T. In the Pr15Co78B7, the Pr2Co14B, PrCo4B and PrCo5 phases co-exist as independent exchange-coupled grains and the weak link was found at the PrCo4B / Pr2Co14B interface, where the reversal interaction domains nucleate and then propagate into Pr2Co14B grains, resulting in a coercivity of approximately 1.2 T. Our experimental findings were compared with micromagnetic modeling, which reveals that the change in the direction of magnetization at the interfaces of exchange-coupled grains often has a very complex topology, and the transition regions between two interaction domains is “pinned” at the structural inhomogeneities. Thus, by using the Pr-Fe-Co-B alloys as a model system, we highlight the significance of gaining a deeper understanding of these processes at the micro- and nano-levels. This knowledge may assist in constructing more accurate models of magnetization reversal in nanocrystalline magnets.

Structural Analysis and Characterization of an Antiproliferative Lectin from Canavalia villosa Seeds.

Cells use glycans to encode information that modulates processes ranging from cell-cell recognition to programmed cell death. This information is encoded within a glycocode, and its decoding is performed by carbohydrate-binding proteins. Among these, lectins stand out due to their specific and reversible interaction with carbohydrates. Changes in glycosylation patterns are observed in several pathologies, including cancer, where abnormal glycans are found on the surfaces of affected tissues. Given the importance of the bioprospection of promising biomolecules, the current work aimed to determine the structural properties and anticancer potential of the mannose-specific lectin from seeds of Canavalia villosa (Cvill). Experimental elucidation of the primary and 3D structures of the lectin, along with glycan array and molecular docking, facilitated the determination of its fine carbohydrate-binding specificity. These structural insights, coupled with the lectin's specificity, have been combined to explain the antiproliferative effect of Cvill against cancer cell lines. This effect is dependent on the carbohydrate-binding activity of Cvill and its uptake in the cells, with concomitant activation of autophagic and apoptotic pathways.

Exceptional n-type thermoelectric ionogels enabled by metal coordination and ion-selective association.

Ionic liquid-based ionogels emerge as promising candidates for efficient ionic thermoelectric conversion due to their quasi-solid state, giant thermopower, high flexibility, and good stability. P-type ionogels have shown impressive performance; however, the development of n-type ionogels lags behind. Here, an n-type ionogel consisting of polyethylene oxide (PEO), lithium salt, and ionic liquid is developed. Strong coordination of lithium ion with ether oxygen and the anion-rich clusters generated by ion-preferential association promote rapid transport of the anions and boost Eastman entropy change, resulting in a huge negative ionic Seebeck coefficient (-15 millivolts per kelvin) and a high electrical conductivity (1.86 millisiemens per centimeter) at 50% relative humidity. Moreover, dynamic and reversible interactions among the ternary mixtures endow the ionogel with fast autonomous self-healing capability and green recyclability. All PEO-based ionic thermoelectric modules are fabricated, which exhibits outstanding thermal responses (-80 millivolts per kelvin for three p-n pairs), demonstrating great potential for low-grade energy harvesting and ultrasensitive thermal sensing.

DNA Chimeras as Electrochemical Biosensors for Host-Guest Measurements in Blood.

Few sensing platforms have become ubiquitous to enable rapid and convenient measurements at the point-of-care. Those, however, are "one-off" technologies, meaning that they can only detect a single target and are hardly adaptable. In response, we plan to develop a sensing platform that can be extended to detect other classes of molecules and that affords rapid, convenient, continuous measurements directly in undiluted complex matrices. For this, we decided to rely on a host molecule that presents reversible interactions toward specific guest molecules to develop a new class of sensors that we coined "Electrochemical DNA-host chimeras". As a proof-of-concept for our sensor, we decided to use cyclobis(paraquat-p-phenylene) ("blue box") that we attached on an electrode-bound DNA to allow measurements of electron-rich guests such as dopamine and aspirin. Doing so allows to promote host-guest complex that could be quantified using blue box's electrochemistry. Because of this unique sensor architecture, we achieve, to our knowledge, the first reagentless, continuous and rapid (< 5 min) host-guest measurements in undiluted whole blood. We envision that given the library of electroactive host molecules that this will allow the development of a sensing platform for measurements of several classes of molecules in complex matrices at the point-of-care.

In-situ phase separation constructing robust hydrophobic ionogels with multifunction

Ionogels, as the promising alternative to hydrogels, have garnered great attention due to their excellent ionic conductivity, thermal stability, and non-volatility. However, the design and construction of robust hydrophobic ionogel still is a significant challenge at present, especially with a facile method. Herein, inspired by the two-phase structure of the dermis in human skin (stiff collagen fiber scaffold embedded in soft elastin matrix), a one-pot in-situ phase separation design strategy is proposed to construct the robust hydrophobic ionogel through the random copolymerization of hydrophobic monomers with the solubility difference in hydrophobic ionic liquid (IL). The resultant ionogel forms a homogeneously dual phase network containing solvent-rich soft domains and solvent-poor hard domains. The mechanical robustness can be synergistically achieved by the hard domain strong skeleton and the soft domain elastic matrix. Benefiting from multiple reversible interactions including hydrogen bonding, ion–dipole and ion-ion interactions, and physical entanglement, the ionogel shows strong IL retention, excellent self-healing, and regenerating abilities, while can adhere to different substrates. The unique phase separation structure brings temperature-dependent transparency and high-damping features. The ionogel also presents high ionic conductivity due to the abundance of movable ions. As application demonstrations, the ionogel is successfully used for dynamic pattern encryption, shock attenuation, and strain sensing. What’s more, this strategy can be also applied to improve the mechanical properties of hydrophobic ionogels based on other monomers. Hence, this work establishes an effective and general design strategy for hydrophobic ionogels demanding versatility.

Metallic-Polyphenolic Nanoparticles Reinforced Cationic Guar Gum Hydrogel for Effectively Treating Burn Wound.

The development of injectable hydrogel dressings which are long-term moisturizing, easy-to-apply, and effectively inhibiting infection and inflammatory is essential to promote burn wound repairing. Herein, an injectable hydrogel with moisturizing, antibacterial, and anti-inflammation abilities via multiple reversible interactions between cation guar gum (CG) and metallic-polyphenolic nanoparticles (PA-ZnII NPs) is developed. Specifically, PA-ZnII NPs is formed by synergistic complexation of protocatechualdehyde (PA) and zinc ion (Zn2+ ), provides CGPZ hydrogel with plentiful reversible interactions to inhibit the loss of moist. By interacting with PA-ZnII NPs, the CGPZ hydrogel can provide enhanced moisturization for more than 3 days. Moreover, the CGPZ hydrogel can maintain good adhesion for a period of time with injection and self-healing capabilities due to reversible interactions between CG and PA-ZnII NPs. In addition, CGPZ hydrogel exhibits outstanding broad spectrum antibacterial performance, as its killing efficiency against Escherichia coli and Staphylococcus aureus is all greater than 99.99%. Importantly, compared with commercial dressing, the CGPZ hydrogel can promote wound healing faster by inhibiting tissue damage from dysregulated inflammation and accelerating neovascularization. It is believed that the moisturizing CGPZ hydrogel with antibacterial and anti-inflammation performance can serve as a promising dressing for the effective treatment of burn wound.

Branched poly-l-lysine for cartilage penetrating carriers.

Joint diseases, such as osteoarthritis, often require delivery of drugs to chondrocytes residing within the cartilage. However, intra-articular delivery of drugs to cartilage remains a challenge due to their rapid clearance within the joint. This problem is further exacerbated by the dense and negatively charged cartilage extracellular matrix (ECM). Cationic nanocarriers that form reversible electrostatic interactions with the anionic ECM can be an effective approach to overcome the electrostatic barrier presented by cartilage tissue. For an effective therapeutic outcome, the nanocarriers need to penetrate, accumulate, and be retained within the cartilage tissue. Nanocarriers that adhere quickly to cartilage tissue after intra-articular administration, transport through cartilage, and remain within its full thickness are crucial to the therapeutic outcome. To this end, we used ring-opening polymerization to synthesize branched poly(l-lysine) (BPL) cationic nanocarriers with varying numbers of poly(lysine) branches, surface charge, and functional groups, while maintaining similar hydrodynamic diameters. Our results show that the multivalent BPL molecules, including those that are highly branched (i.e., generation two), can readily adhere and transport through the full thickness of cartilage, healthy and degenerated, with prolonged intra-cartilage retention. Intra-articular injection of the BPL molecules in mouse knee joint explants and rat knee joints showed their localization and retention. In summary, this study describes an approach to design nanocarriers with varying charge and abundant functional groups while maintaining similar hydrodynamic diameters to aid the delivery of macromolecules to negatively charged tissues.