Biological Utility of Fluorinated Compounds: from Materials Design to Molecular Imaging, Therapeutics and Environmental Remediation.

The applications of fluorinated molecules in bioengineering and nanotechnology are expanding rapidly with the controlled introduction of fluorine being broadly studied due to the unique properties of C-F bonds. This review will focus on the design and utility of C-F containing materials in imaging, therapeutics, and environmental applications with a central theme being the importance of controlling fluorine-fluorine interactions and understanding how such interactions impact biological behavior. Low natural abundance of fluorine is shown to provide sensitivity and background advantages for imaging and detection of a variety of diseases with 19F magnetic resonance imaging, 18F positron emission tomography and ultrasound discussed as illustrative examples. The presence of C-F bonds can also be used to tailor membrane permeability and pharmacokinetic properties of drugs and delivery agents for enhanced cell uptake and therapeutics. A key message of this review is that while the promise of C-F containing materials is significant, a subset of highly fluorinated compounds such as per- and polyfluoroalkyl substances (PFAS), have been identified as posing a potential risk to human health. The unique properties of the C-F bond and the significant potential for fluorine-fluorine interactions in PFAS structures necessitate the development of new strategies for facile and efficient environmental removal and remediation. Recent progress in the development of fluorine-containing compounds as molecular imaging and therapeutic agents will be reviewed and their design features contrasted with environmental and health risks for PFAS systems. Finally, present challenges and future directions in the exploitation of the biological aspects of fluorinated systems will be described.

Ultra-stable all-solid-state sodium metal batteries enabled by perfluoropolyether-based electrolytes.

Rechargeable batteries paired with sodium metal anodes are considered to be one of the most promising high-energy and low-cost energy-storage systems. However, the use of highly reactive sodium metal and the formation of sodium dendrites during battery operation have caused safety concerns, especially when highly flammable liquid electrolytes are used. Here we design and develop solvent-free solid polymer electrolytes (SPEs) based on a perfluoropolyether-terminated polyethylene oxide (PEO)-based block copolymer for safe and stable all-solid-state sodium metal batteries. Compared with traditional PEO SPEs, our results suggest that block copolymer design allows for the formation of self-assembled nanostructures leading to high storage modulus at elevated temperatures with the PEO domains providing transport channels even at high salt concentration (ethylene oxide/sodium = 8/2). Moreover, it is demonstrated that the incorporation of perfluoropolyether segments enhances the Na+ transference number of the electrolyte to 0.46 at 80 °C and enables a stable solid electrolyte interface. The new SPE exhibits highly stable symmetric cell-cycling performance at high current density (0.5 mA cm-2 and 1.0 mAh cm-2, up to 1,000 h). Finally, the assembled all-solid-state sodium metal batteries demonstrate outstanding capacity retention, long-term charge/discharge stability (Coulombic efficiency, 99.91%; >900 cycles with Na3V2(PO4)3 cathode) and good capability with high loading NaFePO4 cathode (>1 mAh cm-2).

Anti-Fouling Surfaces for Extracorporeal Membrane Oxygenation by Surface Grafting of Hydrophilic Sulfoxide Polymers.

Non-thrombogenic surfaces for extracorporeal membrane oxygenation (ECMO) devices are important to increase their duration of usage and to enable long-term life support. However, the contact of blood with the hydrophobic synthetic ECMO membrane materials such as poly(4-methyl-1-pentene) (PMP) can activate the coagulation cascade, causing thrombosis and a series of consequent complications during ECMO operation. Targeting this problem, we proposed to graft highly hydrophilic sulfoxide polymer brushes onto the PMP surfaces via gamma ray irradiation-initiated polymerization to improve the hemocompatibility of the membrane. Through this chemical modification, the surface of the PMP film is altered from hydrophobic to hydrophilic. The extent of plasma protein adsorption and platelet adhesion, the prerequisite mediators of the coagulation cascade and thrombus formation, are drastically reduced compared with those of the unmodified PMP film. Therefore, the method provides a facile approach to modify PMP materials with excellent antifouling properties and improved hemocompatibility demanded by the applications in ECMO and other blood-contacting medical devices.

Low-Fouling Gold Nanorod Theranostic Agents Enabled by a Sulfoxide Polymer Coating.

Gold nanorods (GNRs) are widely used in various biomedical applications such as disease imaging and therapy due to their unique plasmonic properties. To improve their bioavailability, GNRs often need to be coated with hydrophilic polymers so as to impart stealth properties. Poly(ethylene glycol) (PEG) has been long used as such a coating material for GNRs. However, there is increasing acknowledgement that the amphiphilic nature of PEG facilitates its interaction with protein molecules, leading to immune recognition and consequent side effects. This has motivated the search for new classes of low-fouling polymers with high hydrophilicity as alternative low-fouling surface coating materials for GNRs. Herein, we report the synthesis, characterization, and application of GNRs coated with highly hydrophilic sulfoxide-containing polymers. We investigated the effect of the sulfoxide polymer coating on the cellular uptake and in vivo circulation time of the GNRs and compared these properties with pegylated GNR counterparts. The photothermal effect and photoacoustic imaging of these polymer-coated GNRs were also explored, and the results show that these GNRs are promising as nanotheranostic particles for the treatment of cancer.

Efficient Removal of Perfluorinated Chemicals from Contaminated Water Sources Using Magnetic Fluorinated Polymer Sorbents.

Efficient removal of per- and polyfluoroalkyl substances (PFAS) from contaminated waters is urgently needed to safeguard public and environmental health. In this work, novel magnetic fluorinated polymer sorbents were designed to allow efficient capture of PFAS and fast magnetic recovery of the sorbed material. The new sorbent has superior PFAS removal efficiency compared with the commercially available activated carbon and ion-exchange resins. The removal of the ammonium salt of hexafluoropropylene oxide dimer acid (GenX) reaches >99 % within 30 s, and the estimated sorption capacity was 219 mg g-1 based on the Langmuir model. Robust and efficient regeneration of the magnetic polymer sorbent was confirmed by the repeated sorption and desorption of GenX over four cycles. The sorption of multiple PFAS in two real contaminated water matrices at an environmentally relevant concentration (1 ppb) shows >95 % removal for the majority of PFAS tested in this study.

Antifouling Surfaces Enabled by Surface Grafting of Highly Hydrophilic Sulfoxide Polymer Brushes.

Antifouling surfaces are important in a broad range of applications. An effective approach to antifouling surfaces is to covalently attach antifouling polymer brushes. This work reports the synthesis of a new class of antifouling polymer brushes based on highly hydrophilic sulfoxide polymers by surface-initiated photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization. The sulfoxide polymer brushes are able to effectively reduce nonspecific adsorption of proteins and cells, demonstrating remarkable antifouling properties. Given the outstanding antifouling behavior of the sulfoxide polymers and versatility of surface-initiated PET-RAFT technology, this work presents a useful and general approach to engineering various material surfaces with antifouling properties, for potential biomedical applications in areas such as tissue engineering, medical implants, and regenerative medicine.

Charge Reversion Simultaneously Enhances Tumor Accumulation and Cell Uptake of Layered Double Hydroxide Nanohybrids for Effective Imaging and Therapy.

Nanotheranostics have been actively sought in precision nanomedicine in recent years. However, insufficient tumor accumulation and limited cell uptake often impede the nanotheranostic efficacy. Herein, pH-sensitive charge-reversible polymer-coated layered double hydroxide (LDH) nanohybrids are devised to possess long circulation in blood but reserve surface charges in the weakly acidic tumor tissue to re-expose therapeutic LDH nanoparticles for enhanced tumor accumulation and cell uptake. In vitro experimental data demonstrate that charge-reversible nanohybrids mitigate the cell uptake in physiological conditions (pH 7.4), but remarkably facilitate internalization by tumor cells after charge reversion in the weakly acidic environment (pH 6.8). More significantly, about 6.0% of injected charge-reversible nanohybrids accumulate in the tumor tissue at 24 h post injection, far higher than the average accumulation (0.7%) reported elsewhere for nanoparticles. This high tumor accumulation clearly shows the tumor tissues in T1 -weighted magnetic resonance imaging. As a consequence, >95% inhibition of tumor growth in the B16F0-bearing mouse model is achieved via only one treatment combining RNAi and photothermal therapy under very mild irradiation (808 nm laser, 0.3 W cm-2 for 180 s). The current research thus demonstrates a new strategy to functionalize nanoparticles and simultaneously enhance their tumor accumulation and cell internalization for effective cancer theranostics.

Use of Microfluidics to Fabricate Bioerodable Lipid Hybrid Nanoparticles Containing Hydromorphone or Ketamine for the Relief of Intractable Pain.

PURPOSE: For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection. METHODS: A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain. RESULTS: The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 µg. Co-administration of ketamine-loaded NPs at 340 µg did not increase the duration of analgesia significantly. CONCLUSIONS: The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.

Low-Fouling Fluoropolymers for Bioconjugation and In†Vivo Tracking.

The conjugation of hydrophilic low-fouling polymers to therapeutic molecules and particles is an effective approach to improving their aqueous stability, solubility, and pharmacokinetics. Recent concerns over the immunogenicity of poly(ethylene glycol) has highlighted the importance of identifying alternative low fouling polymers. Now, a new class of synthetic water-soluble homo-fluoropolymers are reported with a sulfoxide side-chain structure. The incorporation of fluorine enables direct imaging of the homopolymer by 19 F MRI, negating the need for additional synthetic steps to attach an imaging moiety. These self-reporting fluoropolymers show outstanding imaging sensitivity and remarkable hydrophilicity, and as such are a new class of low-fouling polymer for bioconjugation and in vivo tracking.

Integrating Fluorinated Polymer and Manganese-Layered Double Hydroxide Nanoparticles as pH-activated 19 F MRI Agents for Specific and Sensitive Detection of Breast Cancer.

19 F magnetic resonance imaging (19 F MRI) agents capable of being activated upon interactions with cancer triggers are attracting increasing attention, although challenges still remain for precise and specific detection of cancer tissues. In this study, a novel hybrid 19 F MRI agent for pH-sensitive detection of breast cancer tissues is reported, a composite system designed by conjugating a perfluoropolyether onto the surface of manganese-incorporated layered double hydroxide (Mn-LDH@PFPE) nanoparticles. The 19 F NMR/MRI signals from aqueous solutions of Mn-LDH@PFPE nanoparticles are quenched at pH 7.4, but "turned on" following a reduction in pH to below 6.5. This is due to partial dissolution of Mn2+ from the Mn-LDH nanoparticles and subsequent reduction in the effect of paramagnetic relaxation. Significantly, in vivo experiments reveal that an intense 19 F MR signal can be detected only in the breast tumor tissue after intravenous injection of Mn-LDH@PFPE nanoparticles due to such a specific activation. Thus pH-activated Mn-LDH@PFPE nanoparticles are a potential "smart" 19 F MRI agent for precise and specific detection of cancer diseases.

Fluorinated Glycopolymers as Reduction-responsive 19F MRI Agents for Targeted Imaging of Cancer.

Imaging agents that can be targeted to specific diseases and respond to the microenvironment of the diseased tissue are of considerable interest due to their potential in diagnosing and managing diseases. Here we report a new class of branched fluorinated glycopolymers as 19F MRI contrast agents that respond to a reductive environment, for targeted imaging of cancer. The fluorinated glycopolymers can be readily prepared by a one-pot RAFT polymerization of glucose- and fluorine-containing monomers in the presence of a disulfide-containing cross-linking monomer. The incorporation of glucose units along the polymer chain enables these fluorinated glycopolymers to effectively target cancer cells due to interactions with the overexpressed sugar transporters present on the cell surface. In addition, the polymers exhibit an enhanced 19F MRI signal in response to a reductive environment, one of the unique hallmarks of many cancer cells, demonstrating their potential as promising candidates for targeted imaging of cancer.

Importance of Thermally Induced Aggregation on 19F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-oxazoline)s.

An understanding of thermally induced aggregation and consequent 19F magnetic resonance imaging (MRI) performance is essential for improved design of thermoresponsive 19F MRI contrast agents. Herein we describe a series of novel thermoresponsive perfluoropolyether (PFPE)-based comb-shaped poly(2-oxazoline)s (POxs) with different side-chain structures (2-methyl- (MeOx), 2-ethyl- (EtOx), and 2-( n-propyl)-2-oxazoline (nPrOx)). The comb polymers were prepared through reversible addition-fragmentation chain transfer (RAFT) polymerization of the respective oligo(2-oxazoline)acrylates using a perfluoropolyether macro-RAFT agent. The fluoropolyether chain end drives aggregation of the polymers, with small aggregates forming at 300 K for both poly(OMeOx5A)9-PFPE and poly(OEtOx4A)9-PFPE. The aggregates decrease in size and display increases in 19F MRI intensity with temperature, and at 350 K the MeOx polymers are in the form of unimers in solution, similar to the oligoethylene glycol (OEG)-based PFPE polymer. Above the TCP of poly(OEtOx4A)9-PFPE, the polymer forms large aggregates, and the 19F MR imaging performance is degraded. Likewise, poly(OnPrOx4A)-PFPE is above the LCST at all temperatures studied (300-350 K), and so weak imaging intensity is obtained. This report of novel thermoresponsive POx-based PFPE polymers highlights the importance of understanding self-association of polymers in solution and provides important insights for the development of "smart" thermoresponsive 19F MRI contrast agents.

Bioconjugation and Fluorescence Labeling of Iron Oxide Nanoparticles Grafted with Bromomaleimide-Terminal Polymers.

Iron oxide nanoparticles have been widely applied in biomedical applications for their unique physical properties. Despite the relatively mature synthetic approaches for iron oxide nanoparticles, surface modification strategies for obtaining particles with satisfactory biofunctionality are still urgently needed to meet the challenge of nanomedicine. Herein, we report a surface modification and biofunctionalization strategy for iron oxide-based magnetic nanoparticles based on a dibromomaleimide (DBM)-terminated polymer with brushed polyethylene glycol (PEG) chains. PEG acrylate and phosphonate monomers, serving as antibiofouling and surface anchoring compartments for iron oxide nanoparticles, were incorporated utilizing a novel DBM containing reversible addition-fragmentation chain transfer (RAFT) agent. The particles prepared through this new surface architecture possessed high colloidal stability in a physiological buffer and the capacity of covalent conjugation with biomolecules for targeting. Cell tracking of the molecular probes was achieved concomitantly by exploiting DBM conjugation-induced fluorescence of the nanoparticles.

Synthesis of Discrete Oligomers by Sequential PET-RAFT Single-Unit Monomer Insertion.

Uniform synthetic polymers with precisely defined molar mass and monomer sequence (primary structure) have many potential high-value applications. However, a robust and versatile synthetic strategy for these materials remains one of the great challenges in polymer synthesis. Herein we describe proof-of-principle experiments for a modular strategy to produce discrete oligomers by a visible-light-mediated radical chain process. We utilize the high selectivity provided by photo-induced electron/energy transfer (PET) activation to develop efficient single unit monomer insertion (SUMI) into reversible addition-fragmentation chain-transfer (RAFT) agents. A variety of discrete oligomers (single unit species, dimers, and, for the first time, trimers) have been synthesized by sequential SUMI in very high yield under mild reaction conditions. The trimers were used as building blocks for the construction of uniform hexamers and graft copolymers with precisely defined branches.

Selective Photoactivation: From a Single Unit Monomer Insertion Reaction to Controlled Polymer Architectures.

Here, we exploit the selectivity of photoactivation of thiocarbonylthio compounds to implement two distinct organic and polymer synthetic methodologies: (1) a single unit monomer insertion (SUMI) reaction and (2) selective, controlled radical polymerization via a visible-light-mediated photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) process. In the first method, precise single unit monomer insertion into a dithiobenzoate with a high reaction yield (>97%) is reported using an organic photoredox catalyst, pheophorbide a (PheoA), under red light irradiation (λmax = 635 nm, 0.4 mW/cm(2)). The exceptional selectivity of PheoA toward dithiobenzoate was utilized in combination with another catalyst, zinc tetraphenylporphine (ZnTPP), for the preparation of a complex macromolecular architecture. PheoA was first employed to selectively activate a dithiobenzoate, 4-cyanopentanoic acid dithiobenzoate, for the polymerization of a methacrylate backbone under red light irradiation. Subsequently, metalloporphyrin ZnTPP was utilized to selectively activate pendant trithiocarbonate moieties for the polymerization of acrylates under green light (λmax = 530 nm, 0.6 mW/cm(2)) to yield well-defined graft co-polymers.

Lipid sulfoxide polymers as potential inhalable drug delivery platforms with differential albumin binding affinity.

Inhalable nanomedicines are increasingly being developed to optimise the pharmaceutical treatment of respiratory diseases. Large lipid-based nanosystems at the forefront of the inhalable nanomedicines development pipeline, though, have a number of limitations. The objective of this study was, therefore, to investigate the utility of novel small lipidated sulfoxide polymers based on poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA) as inhalable drug delivery platforms with tuneable membrane permeability imparted by differential albumin binding kinetics. Linear PMSEA (5 kDa) was used as a hydrophilic polymer backbone with excellent anti-fouling and stealth properties compared to poly(ethylene glycol). Terminal lipids comprising single (1C2, 1C12) or double (2C12) chain diglycerides were installed to provide differing affinities for albumin and, by extension, albumin trafficking pathways in the lungs. Albumin binding kinetics, cytotoxicity, lung mucus penetration and cellular uptake and permeability through key cellular barriers in the lungs were examined in vitro. The polymers showed good mucus penetration and no cytotoxicity over 24 h at up to 1 mg ml-1. While 1C2-showed no interaction with albumin, 1C12-PMSEA and 2C12-PMSEA bound albumin with KD values of approximately 76 and 10 µM, respectively. Despite binding to albumin, 2C12-PMSEA showed reduced cell uptake and membrane permeability compared to the smaller polymers and the presence of albumin had little effect on cell uptake and membrane permeability. While PMSEA strongly shielded these lipids from albumin, the data suggest that there is scope to tune the lipid component of these systems to control membrane permeability and cellular interactions in the lungs to tailor drug disposition in the lungs.

Magnetic iron oxide nanoparticles for brain imaging and drug delivery.

Central nervous system (CNS) disorders affect as many as 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment of CNS disorders. With the advent of nanotechnologies, controlled delivery of drugs with nanoparticles holds great promise in CNS disorders for overcoming the blood-brain barrier (BBB) and improving delivery efficacy. In recent years, magnetic iron oxide nanoparticles (MIONPs) have stood out as a promising theranostic nanoplatform for brain imaging and drug delivery as they possess unique physical properties and biodegradable characteristics. In this review, we summarize the recent advances in MIONP-based platforms as imaging and drug delivery agents for brain diseases. We firstly introduce the methods of synthesis and surface functionalization of MIONPs with emphasis on the inclusion of biocompatible polymers that allow for the addition of tailored physicochemical properties. We then discuss the recent advances in in vivo imaging and drug delivery applications using MIONPs. Finally, we present a perspective on the remaining challenges and possible future directions for MIONP-based brain delivery systems.

Fluoropolymer-MOF Hybrids with Switchable Hydrophilicity for 19F MRI-Monitored Cancer Therapy.

Cancer theranostics that combines cancer diagnosis and therapy is a promising approach for personalized cancer treatment. However, current theranostic strategies suffer from low imaging sensitivity for visualization and an inability to target the diseased tissue site with high specificity, thus hindering their translation to the clinic. In this study, we have developed a tumor microenvironment-responsive hybrid theranostic agent by grafting water-soluble, low-fouling fluoropolymers to pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoparticles by surface-initiated RAFT polymerization. The conjugation of the fluoropolymers to ZIF-8 nanoparticles not only allows sensitive in vivo visualization of the nanoparticles by 19F MRI but also significantly prolongs their circulation time in the bloodstream, resulting in improved delivery efficiency to tumor tissue. The ZIF-8-fluoropolymer nanoparticles can respond to the acidic tumor microenvironment, leading to progressive degradation of the nanoparticles and release of zinc ions as well as encapsulated anticancer drugs. The zinc ions released from the ZIF-8 can further coordinate to the fluoropolymers to switch the hydrophilicity and reverse the surface charge of the nanoparticles. This transition in hydrophilicity and surface charge of the polymeric coating can reduce the "stealth-like" nature of the agent and enhance specific uptake by cancer cells. Hence, these hybrid nanoparticles represent intelligent theranostics with highly sensitive imaging capability, significantly prolonged blood circulation time, greatly improved accumulation within the tumor tissue, and enhanced anticancer therapeutic efficiency.

Antifouling and Antibacterial Surfaces Grafted with Sulfur-Containing Copolymers.

Antifouling and antibacterial surfaces that can prevent nonspecific biological adhesion are important to support a myriad of biomedical applications. In this study, we have used an innovative photopolymerization technology to develop sulfur-containing polymer-grafted antifouling and antibacterial surfaces. The relationship between the hydrophilic property and the capability to resist protein and macrophage adsorption of the surface copolymer brushes was investigated. The sulfide monomer incorporated into the surface copolymer brushes can be further ionized to carry positive charges and impart antibacterial activity, leading to surfaces with dual antifouling and antibacterial functions. We believe that the reported sulfur-containing polymer brushes can be considered an emerging and important polymer for antifouling and antibacterial applications.

Development of a hyperbranched polymer-based methotrexate nanomedicine for rheumatoid arthritis.

Methotrexate (MTX) is an effective disease modifying anti-rheumatic drug, but can cause significant hepatotoxicity and liver failure in some individuals. The goal of this work was to develop a MTX-conjugated hyperbranched polymeric nanoparticle based on oligo(ethylene glycol) methyl ether methacrylate (OEGMA) and examine its ability to selectively deliver MTX to rheumatic joints while sparing the liver. MTX was conjugated to the hyperbranched polymer via a matrix metalloproteinase-13 cleavable peptide linker. Two populations of nanoparticles were produced, with sizes averaging 20 and 200nm. Tri-peptide (FFK)-modified MTX was liberated in the presence of matrix metalloproteinase 13 (MMP-13)and showed 100 to 1000-fold lower antiproliferative capacity in monocytic THP-1 cells compared to unmodified MTX, depending on whether the gamma-carboxylate of MTX was functionalized with O-tert-butyl. Nanoparticles showed prolonged plasma exposure after intravenous injection with a terminal half-life of approximately 1 day, but incomplete (50%) absorption after subcutaneous administration. Nanoparticles selectively accumulated in inflamed joints in a rat model of rheumatoid arthritis and showed less than 5% biodistribution in the liver after 5 days. MTX-OtBu nanoparticles also showed no hepatocellular toxicity at 500 µM MTX equivalents. This work provides support for the further development of OEGMA-based hyperbranched polymers as MTX drug delivery systems for rheumatoid arthritis. STATEMENT OF SIGNIFICANCE: Nanomedicines containing covalently conjugated methotrexate offer the potential for selective accumulation of the potent hepatotoxic drug in rheumatic joints and limited liver exposure. One limitation of the high surface presentation of methotrexate on a nanoparticle surface, however, is the potential for enhanced liver uptake. We developed several OEGMA-based hyperbranched polymers containing alpha-carboxyl modified and unmodified methotrexate conjugated via an MMP-13 cleavable hexapeptide linker. The modified methotrexate polymer showed promising in vitro and in vivo behavior warranting further development and optimization as an anti-rheumatic nanomedicine. This work presents a new avenue for further research into the development of hyperbranched polymers for rheumatoid arthritis and suggests interesting approaches that may overcome some limitations associated with the translation of anti-rheumatic nanomedicines into patients.