Hyaluronic acid-coated polypeptide nanogel enhances specific distribution and therapy of tacrolimus in rheumatoid arthritis.

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels' disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.

Novel Fabrication of Bio-polymeric Nanogel Loaded with Nalidixic Acid Formulations for the Effective Prevention of Bacterial Pathogens Leading Urinary Tract Infection and Its Biosafety Evaluation.

Management of urinary tract infections (UTI) is a highly challenging process due to the biofilm-forming ability of human-pathogenic bacteria. Here, we designed to fabricate an effective nanogel with a combination of chitosan bio-polymer and nalidixic acid to prevent biofilm-forming bacterial pathogens. Chitosan-coated nalidixic acid nanogel (NA@CS) exhibits outstanding inhibition potential against bacterial strains. In vitro, anti-bacterial analysis methods (well diffusion, colony-forming assay, and anti-biofilm assay) were performed to study the bacterial inhibition potential of prepared nanogel, which reveals that NA@CS nanogel have greater inhibition potential against selected pathogens. The combination of nalidixic acid with chitosan biopolymer decreases the virulence and pathogenicity of biofilm-forming pathogens due to their ability to membrane phospholipids penetration. Furthermore, the fabricated NA@CS nanogel showed reliable in vitro bio-compatibility on L929 fibroblast cells and in vivo compatibility with Artemia salina animal model. Overall, the results demonstrate that NA@CS nanogel could be an effective therapeutic for treating urinary tract infections and urine bladder wound healing.

Harnessing the CD44-targeted delivery of self-assembled hyaluronan nanogel to reverse the antagonism between Cisplatin and Gefitinib in NSCLC cancer therapy.

The combination of the standard platinum-based chemotherapy with EGFR-tyrosine kinase inhibitor Gefitinib (Gef) principally boosts the anticancer efficacy of advanced non-small cell lung cancer (NSCLC) through non-overlapping mechanisms of action, however the clinical trials of cisplatin (Cis) and Gef combination failed to show a therapeutic improvement likely due to compromised cellular influx of Cis with the Gef interference. To overcome the antagonism between Cis and Gef in anti-NSCLC therapy, here we demonstrated a self-targeted hyaluronan (HA) nanogel to facilitate the anticancer co-delivery by utilizing the HA's intrinsic targeting towards CD44, a receptor frequently overexpressed on lung cancer cells. The co-assembly between HA, Cis and Gef generated a HA/Cis/Gef nanogel of 177.8 nm, featuring a prolonged drug release. Unlike the Gef inhibited the Cis uptake, the HA/Cis/Gef nanogel efficiently facilitated the drug internalization through CD44-targeted delivery as verified by HA competition and CD44 knocking down in H1975 NSCLC model both in vitro and in vivo. Moreover, the HA/Cis/Gef nanogel significantly improved the anticancer efficacy and meanwhile diminished the side effects in reference to the combination of free Cis and Gef. This CD44-targeted HA/Cis/Gef nanogel provided a potent strategy to advance the platinum-based combination therapy towards optimized NSCLC therapy.

Recent advances in near-infrared stimulated nanohybrid hydrogels for cancer photothermal therapy.

Nanomedicine has emerged as a promising avenue for advancing cancer treatment, but the challenge of mitigating its in vivo side effects necessitates the development of innovative structures and materials. Recent investigation has unveiled nanogels as particularly compelling candidates, characterized by a porous, three-dimensional network architecture that exhibits exceptional drug loading capacity. Beyond this, nanogels boast a substantial specific surface area and can be tailored with specific chemical functionalities. Consequently, nanogels are frequently engineered as a multi-modal synergistic platform for combating cancer, wherein photothermal therapy stands out due to its capacity to penetrate deep tissues and achieve localized tumor eradication through the application of elevated temperatures. In this review, we delve into the synthesis of diverse varieties of photothermal nanogels capable of controlled drug release triggered by either chemical or physical stimuli. It also summarizes their potential for synergistic integration with photothermal therapy alongside other therapeutic modalities to realize effective tumor ablation. Moreover, we analyze the primary mechanisms underlying the contribution of photothermal nanogels to cancer treatment while underscoring their adeptness in regulating therapeutic temperatures for repairing bone defects resulting from tumor-associated trauma. Envisioned as an auspicious strategy in the realm of cancer therapy, photothermal nanogels hold promise for furnishing controlled drug delivery and precise thermal ablation capabilities.

Magnetic iron oxide nanogels for combined hyperthermia and drug delivery for cancer treatment.

Hyperthermia and chemotherapy represent potential modalities for cancer treatments. However, hyperthermia can be invasive, while chemotherapy drugs often have severe side effects. Recent clinical investigations have underscored the potential synergistic efficacy of combining hyperthermia with chemotherapy, leading to enhanced cancer cell killing. In this context, magnetic iron oxide nanogels have emerged as promising candidates as they can integrate superparamagnetic iron oxide nanoparticles (IONPs), providing the requisite magnetism for magnetic hyperthermia, with the nanogel scaffold facilitating smart drug delivery. This review provides an overview of the synthetic methodologies employed in fabricating magnetic nanogels. Key properties and designs of these nanogels are discussed and challenges for their translation to the clinic and the market are summarised.

Radiofrequency-responsive black phosphorus nanogel crosslinked with cisplatin for precise synergy in multi-modal tumor therapies.

Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application.

Multiresponsive Nanogels for the Selective Delivery of Antimicrobial Drugs to Mucosal Tissues.

Effective drug delivery to bacterially infected mucosa remains a challenge due to the combined obstacles of the mucosal barrier, pH variations, and high concentrations of glutathione. However, polysaccharide-based responsive nanogels (NGs) can take advantage of these conditions to deliver specific antimicrobials. We explored the critical features of pH- and redox-responsive NGs to increase drug penetration, residence time, and efficacy in the infected mucosa. We prepared multifunctional NGs using hydroxypropyl cellulose as a template for the cross-linking of methacrylic acid with N,N'-bis(acryloyl)cystamine (BAC) or N,N'-methylenebis(acrylamide) (BIS). Studies of NG-mucin binding and the antibacterial efficacy of doxycycline-loaded NGs revealed the interplay between the response to pH and redox clues. Specifically, higher BAC composition increased mucus binding and controlled release in reductive conditions, while higher BIS composition yielded NGs with higher doxycycline-mediated antibacterial efficacy against Staphylococcus aureus. The findings reveal the potential of multiresponsive NGs in effective antimicrobial delivery in infected mucosa.

Development of a skeletal muscle sheet with direct reprogramming-induced myoblasts on a nanogel-cross-linked porous freeze-dried gel scaffold in a mouse gastroschisis model.

PURPOSE: In this study, we attempted to create skeletal muscle sheets made of directly converted myoblasts (dMBs) with a nanogel scaffold on a biosheet using a mouse gastroschisis model. METHODS: dMBs were prepared by the co-transfection of MYOD1 and MYCL into human fibroblasts. Silicon tubes were implanted under the skin of NOG/SCID mice, and biosheets were formed. The nanogel was a nanoscale hydrogel based on cholesterol-modified pullulan, and a NanoClip-FD gel was prepared by freeze-drying the nanogel. 7 mm in length was created in the abdominal wall of NOG/SCID mice as a mouse gastroschisis model. Matrigel or NanoCliP-FD gel seeded with dMBs was placed on the biosheet and implanted on the model mice. RESULTS: Fourteen days after surgery, dMBs with Matrigel showed a small amount of coarse aggregations of muscle-like cells. In contrast, dMBs with NanoCliP-FD gel showed multinucleated muscle-like cells, which were expressed as desmin and myogenin by fluorescent immunostaining. CONCLUSION: Nanogels have a porous structure and are useful as scaffolds for tissue regeneration by supplying oxygen and nutrients supply to the cells. Combining dMBs and nanogels on the biosheets resulted in the differentiation and engraftment of skeletal muscle, suggesting the possibility of developing skeletal muscle sheets derived from autologous cells and tissues.

Dexamethasone-loaded ROS stimuli-responsive nanogels for topical ocular therapy of corneal neovascularization.

Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin ß1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance.

Pongamia pinnata seed extract-mediated green synthesis of silver nanoparticle loaded nanogel for estimation of their antipsoriatic properties.

This research describes the eco-friendly green synthesis of silver nanoparticles employing Pongamia pinnata seed extracts loaded with nanogel formulations (AgNPs CUD NG) to improve the retention, accumulation, and the penetration of AgNPs into the epidermal layer of psoriasis. AgNPs were synthesized using the Box-Behnken design. Optimized AgNPs and AgNPs CUD NG were physico-chemically evaluated using UV-vis spectroscopy, SEM, FT-IR, PXRD, viscosity, spreadability, and retention studies. It was also functionally assessed using an imiquimod-induced rat model. The entrapment efficiency of AgNPs revealed ~ 79.35%. Physico-chemical parameters announced the formation of AgNPs via surface plasmon resonance and interaction between O-H, C = O, and amide I carbonyl group of protein extract and AgNO3. Optimized AgNPs showed spherical NPs ~ 116 nm with better physical stability and suitability for transdermal applications. AgNPs CUD NG revealed non-Newtonian, higher spreadability, and better extrudability, indicating its suitability for a transdermal route. AgNPs CUD NG enhanced the retention of AgNPs on the psoriatic skin compared to normal skin. Optimized formulations exhibit no irritation by the end of 72 h, indicating formulation safety. AgNPs CUD NG at a dose of 1 FTU showed significant recovery from psoriasis with a PASI score of ~ 0.8 compared to NG base and marketed formulations. Results indicated that seed extract-assisted AgNPs in association with CUD-based NG formulations could be a promising nanocarrier for psoriasis and other skin disorders.

Theranostic nanogels: multifunctional agents for simultaneous therapeutic delivery and diagnostic imaging.

In recent years, there has been a growing interest in multifunctional theranostic agents capable of delivering therapeutic payloads while facilitating simultaneous diagnostic imaging of diseased sites. This approach offers a comprehensive strategy particularly valuable in dynamically evolving diseases like cancer, where combining therapy and diagnostics provides crucial insights for treatment planning. Nanoscale platforms, specifically nanogels, have emerged as promising candidates due to their stability, tunability, and multifunctionality as carriers. As a well-studied subgroup of soft polymeric nanoparticles, nanogels exhibit inherent advantages due to their size and chemical compositions, allowing for passive and active targeting of diseased tissues. Moreover, nanogels loaded with therapeutic and diagnostic agents can be designed to respond to specific stimuli at the disease site, enhancing their efficacy and specificity. This capability enables fine-tuning of theranostic platforms, garnering significant clinical interest as they can be tailored for personalized treatments. The ability to monitor tumor progression in response to treatment facilitates the adaptation of therapies according to individual patient responses, highlighting the importance of designing theranostic platforms to guide clinicians in making informed treatment decisions. Consequently, the integration of therapy and diagnostics using theranostic platforms continues to advance, offering intelligent solutions to address the challenges of complex diseases such as cancer. In this context, nanogels capable of delivering therapeutic payloads and simultaneously armed with diagnostic modalities have emerged as an attractive theranostic platform. This review focuses on advances made toward the fabrication and utilization of theranostic nanogels by highlighting examples from recent literature where their performances through a combination of therapeutic agents and imaging methods have been evaluated.

Facile synthesis of elastin nanogels encapsulated decursin for castrated resistance prostate cancer therapy.

Nanogels offer hope for precise drug delivery, while addressing drug delivery hurdles is vital for effective prostate cancer (PCa) management. We developed an injectable elastin nanogels (ENG) for efficient drug delivery system to overcome castration-resistant prostate cancer (CRPC) by delivering Decursin, a small molecule inhibitor that blocks Wnt/ßcatenin pathways for PCa. The ENG exhibited favourable characteristics such as biocompatibility, flexibility, and low toxicity. In this study, size, shape, surface charge, chemical composition, thermal stability, and other properties of ENG were used to confirm the successful synthesis and incorporation of Decursin (DEC) into elastin nanogels (ENG) for prostate cancer therapy. In vitro studies demonstrated sustained release of DEC from the ENG over 120 h, with a pH-dependent release pattern. DU145 cell line induces moderate cytotoxicity of DEC-ENG indicates that nanomedicine has an impact on cell viability and helps strike a balance between therapeutics efficacy and safety while the EPR effect enables targeted drug delivery to prostate tumor sites compared to free DEC. Morphological analysis further supported the effectiveness of DEC-ENG in inducing cell death. Overall, these findings highlight the promising role of ENG-encapsulated decursin as a targeted drug delivery system for CRPC.

Nanoscopic gel particle for intra-articular injection formulation.

Hyaluronic acid (HA) based nanogels showed effective intracellular delivery efficacy for anti-cancer and anti-inflammatory drugs, characterized by their ability targeting relevant cell receptors. In the present study, we demonstrate the ability of hyaluronic acid-polyethyleneimine (HA-PEI) nanogels as a promising dual-functional interfacial active for intra-articular injection to intervene arthritis. Nanomechanical measurements on both model substrates and human cartilage samples confirm that the HA-PEI nanogels can significantly improve interfacial lubrication, in comparison to HA molecules, or silica-based nanoparticles. We show that the Coefficient of Friction significantly decreases with a decreasing nanogel size. The exceptional lubricating performance, coupled with the proven drug delivery capability, evidences the great potential of nanoscopic hydrogels for early-stage arthritis treatment. The flexibility in choosing the chemical nature, molecular architecture, and structural characteristics of nanogels makes it possible to modulate both drug delivery kinetics and interfacial lubrication, thus representing an innovative approach to treat degenerative joint diseases.

A dual-prodrug nanogel combining Vorinostat and Pyropheophorbide a for a high efficient photochemotherapy.

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.

Supramolecularly-Cross-Linked Nanogel Assemblies for On-Demand, Ultrasound-Triggered Chemotherapy.

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.

pH-Induced conversion of bolaamphiphilic vesicles to reduction-responsive nanogels for enhanced Nile Red and Rose Bengal delivery.

This study details the preparation and investigation of molecular nanogels formed by the self-assembly of bolaamphiphilic dipeptide derivatives containing a reduction-sensitive disulfide unit. The described bolaamphiphiles, featuring amino acid terminal groups, generate cationic vesicles at pH 4, which evolve into gel-like nanoparticles at pH 7. The critical aggregation concentration has been determined, and the nanogels' size and morphology have been characterized through Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). Circular Dichroism (CD) spectroscopy reveals substantial molecular reconfigurations accompanying the pH shift. These nanogels enhance the in vitro cellular uptake of the lipophilic dye Nile Red and the ionic photosensitizer Rose Bengal into Human colon adenocarcinoma (HT-29) cells, eliminating the need for organic co-solvents in the former case. Fluorescence measurements with Nile Red as a probe indicate the reduction-sensitive disassembly of the nanogels. In photodynamic therapy (PDT) applications, Rose Bengal-loaded nanogels demonstrate notable improvements, with flow cytometry analysis evidencing increased apoptotic activity in the study with HT-29 cells.

Construction and performance evaluation of polyguluronic acid polysaccharides-based drug delivery systems.

Polysaccharides have garnered significant attention as potential nanoparticle carriers for targeted tumor therapy due to their excellent biodegradability and biocompatibility. Polyguluronic acid (PG) is a homogeneous acidic polysaccharide fragment derived from alginate, which is found in brown algae, possesses excellent bioactivities, unique properties. This study explored the immunomodulatory activity of PG and developed PG-based nanogels through modified disulfide bonds and Ca2+ dual crosslinking. We characterized their structure, assessed their drug-loading and release properties, and ultimately validated both the safety of the nanocarrier and the in vitro anti-tumor efficacy of the encapsulated drug. Results indicated that PG significantly enhanced the proliferative activity and phagocytosis of RAW264.7 cells while promoting reactive oxygen species (ROS) production and cytokine secretion. The study identified TLR4 as the primary receptor for PG recognition in RAW264.7 cells. Furthermore, PG-based drug-carrying nanogels were prepared, exhibiting uniform sizes of about 184 nm and demonstrating exceptional encapsulation efficiency (82.15 ± 0.82 %) and drug loading capacity (8.12 ± 0.08 %). In vitro release experiments showed that these nanogels could responsively release drugs under conditions of high glutathione (GSH) reduction, facilitating drug accumulation at tumor sites and enhancing therapeutic efficacy. This research not only expands the application of PG in drug delivery systems but also provides valuable insights into leveraging natural immunomodulatory polysaccharides as carriers for targeted drug delivery.

Florfenicol core-shell composite nanogels as oral administration for efficient treatment of bacterial enteritis.

To reduce the bitterness of florfenicol, avoid its degradation by gastric acid, and enhance its antibacterial activity against Escherichia coli by targeting and slowly releasing drugs at the site of intestinal infection, with pectin as an anion carrier and chitosan oligosaccharides (COS) as a cationic carrier, florfenicol-loaded COS@pectin core nanogels were self-assembled by electrostatic interaction and then encapsulated in sodium carboxymethylcellulose (CMCNa) shell nanogels through the complexation of CMCNa and Ca2+ to prepare florfenicol core-shell composite nanogels in this study. The florfenicol core-shell composite nanogels were investigated for their formula choice, physicochemical characterization, pH-responsive performances, antibacterial activity, therapeutic efficacy, and in vitro and in vivo biosafety studies. The results indicated that the optimized formula was 0.6 g florfenicol, 0.79 g CMCNa, 0.30 g CaCl2, 0.05 g COS, and 0.10 g pectin, respectively. In addition, the mean particle diameter, polydispersity index, zeta potential, loading capacity, and encapsulation efficiency were 124.0 ± 7.2 nm, -22.9 ± 2.5 mV, 0.42 ± 0.03, 43.4 % ± 3.1 %, and 80.5 % ± 3.4 %, respectively. The appearance, lyophilized mass, resolvability, scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (PXRD), and fourier transform infrared (FTIR) showed that the florfenicol core-shell composite nanogels were successfully prepared. Florfenicol core-shell composite nanogels had satisfactory stability, rheology, and pH-responsiveness, which were conducive to avoid degradation by gastric acid and achieve targeted and slow release at intestinal infection sites. More importantly, florfenicol core-shell composite nanogels had excellent antibacterial activity against Escherichia coli, a satisfactory therapeutic effect, and good palatability. In vitro and in vivo biosafety studies suggested the great promise of florfenicol core-shell composite nanogels. Therefore, the prepared florfenicol core-shell composite nanogels may be helpful for the treatment of bacterial enteritis as a biocompatible oral administration.

Dhvar5-chitosan nanogels and their potential to improve antibiotics activity.

Infection is one of the main causes of orthopedic implants failure, with antibiotic-resistant bacteria playing a crucial role in this outcome. In this work, antimicrobial nanogels were developed to be applied in situ as implant coating to prevent orthopedic-device-related infections. To that regard, a broad-spectrum antimicrobial peptide, Dhvar5, was grafted onto chitosan via thiol-norbornene "photoclick" chemistry. Dhvar5-chitosan nanogels (Dhvar5-NG) were then produced using a microfluidic system. Dhvar5-NG (1010 nanogels (NG)/mL) with a Dhvar5 concentration of 6 µg/mL reduced the burden of the most critical bacteria in orthopedic infections - methicillin-resistant Staphylococcus aureus (MRSA) - after 24 h in medium supplemented with human plasma proteins. Transmission electron microscopy showed that Dhvar5-NG killed bacteria by membrane disruption and cytoplasm release. No signs of cytotoxicity against a pre-osteoblast cell line were verified upon incubation with Dhvar5-NG. To further explore therapeutic alternatives, the potential synergistic effect of Dhvar5-NG with antibiotics was evaluated against MRSA. Dhvar5-NG at a sub-minimal inhibitory concentration (109 NG/mL) demonstrated synergistic effect with oxacillin (4-fold reduction: from 2 to 0.5 µg/mL) and piperacillin (2-fold reduction: from 2 to 1 µg/mL). This work supports the use of Dhvar5-NG as adjuvant of antibiotics to the prevention of orthopedic devices-related infections.

Rosmarinic acid-grafted gelatin nanogels for efficient diquafosol delivery in dry eye disease therapy.

Dry eye disease (DED) is a prevalent ocular disorder characterized by unstable tear film condition with loss of aqueous or mucin, excessive oxidative stress, and inflammation, leading to discomfort and potential damage to the ocular surface. Current DED therapies have shown restricted therapeutic effects such as frequent dosing and temporary relief with potential unwanted side effects, urgently necessitating the development of innovative efficient therapeutic approaches. Herein, we developed rosmarinic acid (RosA) conjugated gelatin nanogels loading diquafosol sodium (DQS), DRGNG, for simultaneous ROS-scavenging and mucin-secreting DED treatment. Mechanically, DRGNG suppressed the ROS production, reduced inflammatory factors, and prompted mucin secretion in vitro and in vivo. The whole transcriptome RNA sequencing in vitro further provided a detailed analysis of the upregulation of anti-oxidant, anti-inflammatory, and mucin-promotion pathways. Therapeutically, both in evaporative DED and aqueous deficient DED models, the dual-functional DRGNG could prolong the retention time at the ocular surface, efficiently suppress the oxidative stress response, reverse ocular surface morphology, and recover tear film homeostasis, thus alleviating the DED when the dosage is halved compared to the commercial Diquas®. Our findings contribute to developing innovative therapies for DED and offer insights into the broader applications of nanogels in ocular drug delivery and oxidative stress-related conditions.