Polymeric Nanogels Research Articles

Molecularly imprinted polymer nanogels targeting the HAV motif in cadherins inhibit cell–cell adhesion and migration

Cadherins are cell-surface proteins that mediate cell-cell adhesion. By regulating their grip formation and strength, cadherins play a pivotal role during normal tissue morphogenesis and homeostasis of multicellular organisms. However, their dysfunction is associated with cell migration and proliferation, cancer progression and metastasis. The conserved amino acid sequence His-Ala-Val (HAV) in the extracellular domain of cadherins is implicated in cadherin-mediated adhesion and migration. Antagonists of cadherin adhesion such as monoclonal antibodies and small molecule inhibitors based on HAV peptides, are of high therapeutic value in cancer treatment. However, antibodies are not stable outside their natural environment and are expensive to produce, while peptides have certain limitations as a drug as they are prone to proteolysis. Herein, we propose as alternative, a synthetic antibody based on molecularly imprinted polymer nanogels (MIP-NGs) to target the HAV domain. The MIP-NGs are biocompatible, have high affinity for N-cadherin and inhibit cell adhesion and migration of human cervical adenocarcinoma (HeLa) cells, as demonstrated by cell aggregation and Matrigel invasion assays, respectively. The emergence of MIPs as therapeutics for fighting cancer is still in its infancy and this novel demonstration reinforces the fact that they have a rightful place in cancer treatment.

In vivo stealthified molecularly imprinted polymer nanogels incorporated with gold nanoparticles for radiation therapy

Radiation therapy is a representative therapeutic approach for cancer treatment, wherein the development of efficient radiation sensitizers with low side effects is critical. In this study, a novel stealth radiation sensitizer based on Au-embedded molecularly imprinted polymer nanogels (Au MIP-NGs) was developed for low-dose X-ray radiation therapy. Surface plasmon resonance measurements reveal the good affinity and selectivity of the obtained Au MIP-NGs toward the target dysopsonic protein, human serum albumin. The protein recognition capability of the nanogels led to the formation of the albumin-rich protein corona in the plasma. The Au MIP-NGs acquire stealth capability in vivo through protein corona regulation using the intrinsic dysopsonic proteins. The injection of Au MIP-NGs improved the efficiency of the radiation therapy in mouse models of pancreatic cancer. The growth of the pancreatic tumor was inhibited even at low X-ray doses (2 Gy). The novel strategy reported in this study for the synthesis of stealth nanomaterials based on nanomaterial-protein interaction control shows significant potential for application even in other approaches for cancer treatment, diagnostics, and theranostics. This strategy paves a way for the development of a wide range of effective nanomedicines for cancer therapy.

Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors.

Rationale: Development of intelligent radiosensitization nanoplatforms for imaging-guided tumor radiotherapy (RT) remains challenging. We report here the construction of an intelligent nanoplatform based on poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO2) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging-guided “full-process” sensitized RT of tumors.Methods: PVCL NGs were synthesized via precipitation polymerization and in situ loaded with Au and MnO2 NPs. The created PVCL-Au-MnO2 NGs were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular oxygen and ·OH production, and cell cycle arrest in vitro, evaluated to disclose their RT sensitization effects of cancer cells and a tumor model, and assessed to validate their dual-mode CT/MR imaging potential, pharmacokinetics, biodistribution, and biosafety in vivo.Results: The formed PVCL-Au-MnO2 NGs with a size of 121.5 nm and good stability can efficiently generate reactive oxygen species through a Fenton-like reaction to result in cell cycle distribution toward highly radiosensitive G2/M phase prior to X-ray irradiation, sensitize the RT of cancer cells under X-ray through the loaded Au NPs to induce the significant DNA damage, and further prevent DNA-repairing process after RT through the continuous production of O2 catalyzed by MnO2 in the hybrid NGs to relieve the tumor hypoxia. Likewise, the in vivo tumor RT can also be guided through dual mode CT/MR imaging due to the Au NPs and Mn(II) transformed from MnO2 NPs.Conclusion: Our study suggests an intelligent PVCL-based theranostic NG platform that can achieve “full-process” sensitized tumor RT under the guidance of dual-mode CT/MR imaging.

Influence of Nanogel Amphiphilicity on Dermal Delivery: Balancing Surface Hydrophobicity and Network Rigidity.

Polymeric nanogels are promising nonirritating nanocarriers for topical delivery applications. However, conventional hydrophilic networks limit encapsulation of hydrophobic therapeutics and hinder tailored interactions with the amphiphilic skin barrier. To address these limitations, we present amphiphilic nanogels containing hydrophilic networks with hydrophobic domains. Two competing factors determine favorable nanogel-skin interactions and need to be balanced through network composition: suitable surface hydrophobicity and low network rigidity (through physical hydrophobic cross-links). To ensure comparability in such investigations, we prepared a library of nanogels with increasing hydrophobic cholesteryl amounts but similar colloidal features. By combining mechanical and surface hydrophobicity tests (atomic force microscopy (AFM)) with dermal delivery experiments on excised human skin, we can correlate an increased delivery efficacy of Nile red to the viable epidermis with a specific network composition, i.e., 20-30 mol % cholesterol. Thus, our nanogel library identifies a specific balance between surface amphiphilicity and network rigidity to guide developments of advanced dermal delivery vehicles.

Macrophage Membrane-Camouflaged Responsive Polymer Nanogels Enable Magnetic Resonance Imaging-Guided Chemotherapy/Chemodynamic Therapy of Orthotopic Glioma.

Development of innovative nanomedicine formulations to traverse the blood-brain barrier (BBB) for effective theranostics of glioma remains a great challenge. Herein, we report the creation of macrophage membrane-camouflaged multifunctional polymer nanogels coloaded with manganese dioxide (MnO2) and cisplatin for magnetic resonance (MR) imaging-guided chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) formed via precipitation polymerization were in situ loaded with MnO2 and physically encapsulated with cisplatin to have a mean size of 106.3 nm and coated with macrophage membranes to have a good colloidal stability. The generated hybrid NGs display dual pH- and redox-responsive cisplatin and Mn(II) release profiles and can deplete glutathione (GSH) rich in tumor microenvironment through reaction with disulfide-containing cross-linkers within the NGs and MnO2. The thus created Mn(II) enables enhanced CDT through a Fenton-like reaction and T1-weighted MR imaging, while the loaded cisplatin not only exerts its chemotherapy effect but also promotes the reactive oxygen species generation to enhance the CDT efficacy. Importantly, the macrophage membrane coating rendered the hybrid NGs with prolonged blood circulation time and ability to traverse BBB for specific targeted chemotherapy/CDT of orthotopic glioma. Our study demonstrates a promising self-adaptive and cooperative NG-based nanomedicine platform for highly efficient theranostics of glioma, which may be extended to tackle other difficult cancer types.

A Triple Culture Cell System Modeling the Human Blood-Brain Barrier

The delivery of drugs to the brain remains a challenge due to the blood-brain barrier's (BBB) highly specific and restrictive properties, which controls and restrict access to the brain parenchyma. However, with the development of nanotechnologies, large panels of new nanomaterials were developed to improve drug delivery, highlighting the need for reliable in vitro microsystems to predict brain penetration in the frame of preclinical assays. Here is a straightforward method to set up a microphysiological system to model the BBB using solely human cells. In its configuration, the model consists of a triple culture including brain-like endothelial cells (BLECs), pericytes, and astrocytes, the three main BBB cellular actors necessary to induce and regulate the BBB properties in a more physiological manner without the requirement of tightening compounds. The model developed in a 12-well plate format, ready after 6 days of triple culture, is characterized in physical properties, gene, and protein expressions and used for polymeric nanogel transport measurement. The model can be used for an extensive range of experiments in healthy and pathological conditions and represents a valuable tool for preclinical assessments of molecule and particle transport, as well as inter-and intracellular trafficking.

A Triple Culture Cell System Modeling the Human Blood-Brain Barrier.

The delivery of drugs to the brain remains a challenge due to the blood-brain barrier's (BBB) highly specific and restrictive properties, which controls and restrict access to the brain parenchyma. However, with the development of nanotechnologies, large panels of new nanomaterials were developed to improve drug delivery, highlighting the need for reliable in vitro microsystems to predict brain penetration in the frame of preclinical assays. Here is a straightforward method to set up a microphysiological system to model the BBB using solely human cells. In its configuration, the model consists of a triple culture including brain-like endothelial cells (BLECs), pericytes, and astrocytes, the three main BBB cellular actors necessary to induce and regulate the BBB properties in a more physiological manner without the requirement of tightening compounds. The model developed in a 12-well plate format, ready after 6 days of triple culture, is characterized in physical properties, gene, and protein expressions and used for polymeric nanogel transport measurement. The model can be used for an extensive range of experiments in healthy and pathological conditions and represents a valuable tool for preclinical assessments of molecule and particle transport, as well as inter-and intracellular trafficking.

Radiation synthesis of poly(acrylic acid) nanogels for drug delivery applications – post-synthesis product colloidal stability

Abstract Synthesis of polymer nanogels (NGs) for biomedical applications is considered to be a very promising application in radiation engineering. Under high-dose pulse irradiation of dilute aqueous polymer solution, reactive species generated by water radiolysis can create multiple radicals on each macromolecule and consequently induce intramolecular cross-linking of polymer chains, resulting in NG formation. The obtained products are free from harmful monomers, initiators, and cross-linking agents, which makes them potentially applicable for drug delivery applications. One of the biggest challenges in handling and use of nanoparticles, however, is the colloidal stability, when aqueous suspensions are stored for prolonged periods. Therefore, development of the best protocols for the particular nanocarrier storage is key. To address this need, we have performed the prospective study in which we systematically assessed the influence of various processing and storage scenarios feasible in our lab, on the colloidal stability of the radiation-synthesized poly(acrylic acid) (PAA) NG particles in suspension. This allowed us to choose the optimal way of handling the product after its synthesis. We confirmed that none of the strategies we used and tested are substantially detrimental to our product. Filtration with 0.2-μm filters was proven sufficient for sample purification and prolonged storage in aqueous suspension did not exert a negative effect on the colloidal stability of particles suspension. We have also demonstrated that lyoprotectant-free lyophilization was suitable for our polymer nanoparticles. This is an important fact for further application of particles as nanocarriers for biologically active compounds such as targeting ligands or therapeutic moieties.

Direct Pore-Level Visualization and Verification of In Situ Oil-in-Water Pickering Emulsification during Polymeric Nanogel Flooding for EOR in a Transparent Three-Dimensional Micromodel.

Different from inorganic nanoparticles, nanosized cross-linked polymeric nanoparticles (nanogels) have been demonstrated to generate more stable Pickering emulsions under harsh conditions for a long term owing to their inherent high hydrophilicity and surface energy. In both core and pore scales, the emulsions are found to be able to form in situ during the nanofluid flooding process for an enhanced oil recovery (EOR) process. Due to the limitation of direct visualization in core scale or deficient pore geometries built by two-dimensional micromodels, the in situ emulsification by nanofluids and emulsion transport are still not being well understood. In this work, we use a three-dimensional transparent porous medium to directly visualize the in situ emulsification during the nanogel flooding process for EOR after water flooding. By synthesizing the nanogel with a fluorescent dye, we find the nanogels adsorbed on the oil-water interface to lower the total interfacial energy and emulsify the large oil droplets into small Pickering oil-in-water emulsions. A potential mechanism for in situ emulsification by nanogels is proposed and discussed. After nanogel flooding, the emulsions trapped in pore throats and those in the effluents are all found encapsulated by the nanogels. After nanogel flooding under different flow rates, the sphericity and diameter changes of remaining oil droplets are quantitatively compared and analyzed using grouped boxplots. It is concluded that in situ emulsification happens during nanogel injection due to the reduction of interfacial tension, which helps to increase the oil recovery rate under different flow rates and pore geometries.

On the Mechanism and Kinetics of Synthesizing Polymer Nanogels by Ionizing Radiation-Induced Intramolecular Crosslinking of Macromolecules.

Nanogels—internally crosslinked macromolecules—have a growing palette of potential applications, including as drug, gene or radioisotope nanocarriers and as in vivo signaling molecules in modern diagnostics and therapy. This has triggered considerable interest in developing new methods for their synthesis. The procedure based on intramolecular crosslinking of polymer radicals generated by pulses of ionizing radiation has many advantages. The substrates needed are usually simple biocompatible polymers and water. This eliminates the use of monomers, chemical crosslinking agents, initiators, surfactants, etc., thus limiting potential problems with the biocompatibility of products. This review summarizes the basics of this method, providing background information on relevant aspects of polymer solution thermodynamics, radiolysis of aqueous solutions, generation and reactions of polymer radicals, and the non-trivial kinetics and mechanism of crosslinking, focusing on the main factors influencing the outcomes of the radiation synthesis of nanogels: molecular weight of the starting polymer, its concentration, irradiation mode, absorbed dose of ionizing radiation and temperature. The most important techniques used to perform the synthesis, to study the kinetics and mechanism of the involved reactions, and to assess the physicochemical properties of the formed nanogels are presented. Two select important cases, the synthesis of nanogels based on polyvinylpyrrolidone (PVP) and/or poly(acrylic acid) (PAA), are discussed in more detail. Examples of recent application studies on radiation-synthesized PVP and PAA nanogels in transporting drugs across the blood–brain barrier and as targeted radioisotope carriers in nanoradiotherapy are briefly described.

Phosphate Polymer Nanogel for Selective and Efficient Rare Earth Element Recovery.

Demand for rare earth elements (REEs) is increasing, and REE production from ores is energy-intensive. Recovering REEs from waste streams can provide a more sustainable approach to help meet REE demand but requires materials with high selectivity and capacity for REEs due to the low concentration of REEs and high competing ion concentrations. Here, we developed a phosphate polymer nanogel (PPN) to selectively recover REEs from low REE content waste streams, including leached fly ash. A high phosphorus content (16.2 wt % P as phosphate groups) in the PPN provides an abundance of coordination sites for REE binding. In model solutions, the distribution coefficient (Kd) for all REEs ranged from 1.3 × 105 to 3.1 × 105 mL g-1 at pH = 7, and the sorption capacity (qm) for Nd, Gd, and Ho were ∼300 mg g-1. The PPN was selective toward REEs, outcompeting cations (Ca, Mg, Fe, Al) at up to 1000-fold excess concentration. The PPN had a Kd of ∼105-106 mL g-1 for lanthanides in coal fly ash leachate (pH = 5), orders of magnitude higher than the Kd of major competing ions (∼103-104 mL g-1). REEs were recovered from the PPN using 3.5% HNO3, and the material remained effective over three sorption-elution cycles. The high REE capacity and selectivity and good durability in a real waste stream matrix suggest its potential to recover REEs from a broad range of secondary REE stocks.

Molecularly Imprinted Polymer Nanogels for Protein Recognition: Direct Proof of Specific Binding Sites by Solution STD and WaterLOGSY NMR Spectroscopies.

Molecularly imprinted polymers (MIPs) are tailor-made synthetic antibodies possessing specific binding cavities designed for a target molecule. Currently, MIPs for protein targets are synthesized by imprinting a short surface-exposed fragment of the protein, called epitope or antigenic determinant. However, finding the epitope par excellence that will yield a peptide "synthetic antibody" cross-reacting exclusively with the protein from which it is derived, is not easy. We propose a computer-based rational approach to unambiguously identify the "best" epitope candidate. Then, using Saturation Transfer Difference (STD) and WaterLOGSY NMR spectroscopies, we prove the existence of specific binding sites created by the imprinting of this peptide epitope in the MIP nanogel. The optimized MIP nanogel could bind the epitope and cognate protein with a high affinity and selectivity. The study was performed on Hepatitis A Virus Cell Receptor-1 protein, also known as KIM-1 and TIM-1, for its ubiquitous implication in numerous pathologies.

Molecularly Imprinted Polymer Nanogels for Protein Recognition: Direct Proof of Specific Binding Sites by Solution STD and WaterLOGSY NMR Spectroscopies

AbstractMolecularly imprinted polymers (MIPs) are tailor‐made synthetic antibodies possessing specific binding cavities designed for a target molecule. Currently, MIPs for protein targets are synthesized by imprinting a short surface‐exposed fragment of the protein, called epitope or antigenic determinant. However, finding the epitope par excellence that will yield a peptide “synthetic antibody” cross‐reacting exclusively with the protein from which it is derived, is not easy. We propose a computer‐based rational approach to unambiguously identify the “best” epitope candidate. Then, using Saturation Transfer Difference (STD) and WaterLOGSY NMR spectroscopies, we prove the existence of specific binding sites created by the imprinting of this peptide epitope in the MIP nanogel. The optimized MIP nanogel could bind the epitope and cognate protein with a high affinity and selectivity. The study was performed on Hepatitis A Virus Cell Receptor‐1 protein, also known as KIM‐1 and TIM‐1, for its ubiquitous implication in numerous pathologies.

Use of pH-Active Catechol-Bearing Polymeric Nanogels with Glutathione-Responsive Dissociation to Codeliver Bortezomib and Doxorubicin for the Synergistic Therapy of Cancer.

Synergistic therapy holds promising potential in cancer treatment. Here, the inclusion of catechol moieties, a disulfide cross-linked structure, and pendent carboxyl into the network of polymeric nanogels with glutathione (GSH)-responsive dissociation and pH-sensitive release is first disclosed for the codelivery of doxorubicin (DOX) and bortezomib (BTZ) in synergistic cancer therapy. The pendent carboxyl groups and catechol moieties are exploited to absorb DOX through electrostatic interaction and conjugate BTZ through boronate ester, respectively. Both electrostatic interactions and boronate ester are stable at neutral or alkaline pH, while they are instable in an acidic environment to further recover the activities of BTZ and DOX. The polymeric nanogels possess a superior stability to prevent the premature leakage of drugs in a physiological environment, while their structure is destroyed in response to a typical endogenous stimulus (GSH) to unload drugs. The dissociation of the drug-loaded nanogels accelerates the intracellular release of DOX and BTZ and further enhances the therapeutic efficacy. In vitro and in vivo investigations revealed that the dual-drug loaded polymeric nanogels exhibited a strong ability to suppress tumor growth. This study thus proposes a new perspective on the production of multifunctional polymeric nanogels through the introduction of different functional monomers.

Exogenous Introduction of Initiator and Executioner Caspases Results in Different Apoptotic Outcomes.

The balance of pro-apoptotic and pro-survival proteins defines a cell’s fate. These processes are controlled through an interdependent and finely tuned protein network that enables survival or leads to apoptotic cell death. The caspase family of proteases is central to this apoptotic network, with initiator and executioner caspases, and their interaction partners, regulating and executing apoptosis. In this work, we interrogate and modulate this network by exogenously introducing specific initiator or executioner caspase proteins. Each caspase is exogenously introduced using redox-responsive polymeric nanogels. Although caspase-3 might be expected to be the most effective due to the centrality of its role in apoptosis and its heightened catalytic efficiency relative to other family members, we observed that caspase-7 and caspase-9 are the most effective at inducing apoptotic cell death. By critically analyzing the introduced activity of the delivered caspase, the pattern of substrate cleavage, as well as the ability to activate endogenous caspases, we conclude that the efficacy of each caspase correlated with the levels of pro-survival factors that both directly and indirectly impact the introduced caspase. These findings lay the groundwork for developing methods for exogenous introduction of caspases as a therapeutic option that can be tuned to the apoptotic balance in a proliferating cell.

Fluorescent Nanodiamond–Nanogels for Nanoscale Sensing and Photodynamic Applications

Nanoscale Sensing In article number 2000101, Fedor Jelezko, Marco Raabe, Tanja Weil, and co-workers establish “adsorption-crosslinking” as new concept to modify nanodiamond surfaces and stabilize them within a crosslinked polymeric nanogel shell. The coated nanodiamonds are internalized into cells thus allowing nanoscale sensing applications. The nanodiamond-nanogels are able to detect paramagnetic ions and magnetic proteins. Moreover, they could be useful for photodynamic applications in combination with ruthenium complexes.

Nanogel-facilitated Protein Intracellular Specific Degradation through Trim-Away.

Recently discovered "Trim-Away" mechanism opens a new window for fast and selective degradation of endogenous proteins. However, the in vivo and clinical application of this approach is stuck by the requirement of special skills and equipment needed for the intracellular delivery of antibodies. Hereby, an antibody conjugated polymer nanogel system, Nano-ERASER, for intracellular delivery and release of antibody, and degradation of a specific endogenous protein has been developed. After being delivered into cells, the antibody is released and forms complex with its target protein, and subsequently binds to the Fc receptor of TRIM21. The resulted complex of target protein/antibody/TRIM21 is then degraded by the proteasome. The efficacy of Nano-ERASER has been validated by depleting GFP protein in a GFP expressing cell line. Furthermore, Nano-ERASER successfully degrades COPZ1, a vital protein for cancer cells, and kills those cells while sparing normal cells. Benefit from its convenience and targeted delivery merit, Nano-ERASER technique is promising in providing a reliable tool for endogenous protein function study as well as paves the way for novel antibody-based Trim-Away therapeutic modalities for cancer and other diseases.

Evaluating Endosomal Escape of Caspase-3-Containing Nanomaterials Using Split GFP.

The ability for biologics to access intracellular targets hinges on the translocation of active, unmodified proteins. This is often achieved using nanoscale formulations, which enter cells through endocytosis. This uptake mechanism often limits the therapeutic potential of the biologics, as the propensity of the nanocarrier to escape the endosome becomes the key determinant. To appropriately evaluate and compare competing delivery systems of disparate compositions, it is therefore critical to assess endosomal escape efficiencies. Unfortunately, quantitative tools to assess endosomal escape are lacking, and standard approaches often lead to an erroneous interpretation of cytosolic localization. In this study we use a split-complementation endosomal escape (SEE) assay to evaluate levels of cytosolic caspase-3 following delivery by polymer nanogels and mesoporous silica nanoparticles. In particular, we use SEE as a means to enable the systematic investigation of the effect of polymer composition, polymer architecture (random vs block), hydrophobicity, and surface functionality. Although polymer structure had little influence on endosomal escape, nanogel functionalization with cationic and pH-sensitive peptides significantly enhanced endosomal escape levels and, further, significantly increased the amount of nanogel per endosome. This work serves as a guide for developing an optimal caspase-3 delivery system, as this caspase-3 variant can be easily substituted for a therapeutic caspase-3 cargo in any system that results in cytosolic accumulation and cargo release. In addition, these data provide a framework that can be readily applied to a wide variety of protein cargos to assess the independent contributions of both uptake and endosomal escape of a wide range of protein delivery vehicles.

"Smart" Polymer Nanogels as Pharmaceutical Carriers: A Versatile Platform for Programmed Delivery and Diagnostics.

“Smart” polymeric nanoformulations are evolving as a promising therapeutic, diagnostic paradigm. The polymeric nanovehicles demonstrated excellent capability to encapsulate theranostic cargos and their successful delivery in physiological conditions and even to monitor the therapeutic response. Currently, polymer nanogels (NGs) are established as capable carriers toward triggered delivery of diverse therapeutic and diagnostic agents. Notably, biodegradable and “intelligent” NGs constructed from intelligent polymers are highly beneficial because of their responsiveness toward endogenous as well as exogenous stimuli like pH gradients, bioresponsiveness, photoresponsiveness, temperature, and so on. In the past decade, plenty of multifunctional NGs with excellent targetability and sensitivity were reported for a wide range of theragnostic applications. This mini-review briefly propounds the synthesis strategies of “smart” NGs and summarizes the notable applications like delivery of genetic materials, anticancer agents, photodynamic/photothermal therapies, imaging, and biosensing. Herein, we have also addressed the current clinical status of NGs and the major challenges that are essential to overcome for the further advancement of NGs for specific applications.

Self-Assembled Thermoresponsive Nanogel from Grafted Hyaluronic Acid as a Biocompatible Delivery Platform for Curcumin with Enhanced Drug Loading and Biological Activities.

A hyaluronic acid-grafted poly(N-isopropylacrylamide) (HA-pNIPAM) was synthesized as a polymeric nanogel platform for encapsulation and delivery of hydrophobic bioactive compounds using curcumin as a model drug. As demonstrated by transmission electron microscopy and dynamic light scattering techniques, the HA-pNIPAM was simply assembled into spherical nano-sized particles with the thermoresponsive behavior. The success of curcumin aqueous solubilization was confirmed by fluorescent spectroscopy. The resulting nanogel formulation enhanced the aqueous solubility and uptake into NIH-3T3 cells of curcumin. This nanogel formulation also demonstrates cytocompatibility against NIH-3T3 cells, which deems it safe as a delivery vehicle. Moreover, the formulation has a slight skin-protection effect using an artificial skin equivalence model. The curcumin-loaded HA-pNIPAM nanogel showed an anti-proliferative activity against MDA-MB-231, Caco-2, HepG2, HT-29, and TNF-α-induced hyperproliferation of keratinocyte (HaCaT) cells. The thermoresponsive HA-pNIPAM nanogel reported here could be further optimized as a platform for controlled-release systems to encapsulate pharmaceuticals for therapeutic applications.