Versatile Drug Delivery System Research Articles

Beyond Creams and Gels: The Emergence of Emulgels in Pharmaceutical Science

Background: Emulgels combine the properties of emulsions and gels, offering a unique drug delivery system that enhances the solubility and stability of hydrophobic drugs. This study reviews recent advancements in emulgels and their potential in pharmaceutical applications. Objective: To systematically review the current state of research on emulgels, focusing on formulation techniques, characterization methods, and therapeutic applications. Methods: A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science, covering studies published from 2010 to 2023. Inclusion criteria included articles discussing formulation techniques, characterization, and therapeutic applications of emulgels. Data extraction and quality assessment were performed independently by two reviewers. Results: Various formulation techniques, such as high-energy emulsification, phase inversion, and solvent evaporation, have been explored to enhance the bioavailability of hydrophobic drugs. Recent advancements introduced novel methods like microfluidization and ultrasound-assisted emulsification to improve formulation efficiency. Characterization techniques, including rheological analysis, particle size determination, and drug release studies, are crucial for optimizing emulgel formulations. Several patents have been filed, reflecting innovative approaches in emulgel technology, such as incorporating nanomaterials and targeted delivery systems. Therapeutic applications of emulgels have been extensively studied in dermatology, pain management, and antimicrobial therapy, showing promising results in enhancing drug efficacy and patient compliance. Conclusion: Emulgels present a versatile and efficient drug delivery system with significant potential in various therapeutic areas. Future research should focus on the large-scale production of emulgels and their long-term stability to facilitate their transition from research to clinical practice.

Self-Assembly of Silole-Based Aggregation-Induced Emission Compounds with Green Fluorescent Protein under Physiological Conditions for Traceable and Versatile Drug Delivery.

Biomacromolecules are viewed as promising drugs due to their specific functions in biological processes, biocompatibility, and pharmacological efficacy. Injective administration, chosen to avoid intestinal barriers, may in turn lead to immediate decay in the circulation system, unreliable targeting performance, or the induction of immune responses. For some biomacromolecules, chemically modified proteins have been developed for practical use. Various cargo or carrier systems are under development but have been delayed by technical difficulties. We present self-assembled nanocapsules with diameters ranging from 100 to 500 nm that can be deployed in physiological buffers to enclose various substances present in the buffers at the same time. Our amphiphilic nanocapsule, consisting of silole-core dendrimer products as the hydrophobic part and green fluorescent protein (GFP) derivatives as the hydrophilic part, connects and assembles spontaneously when mixed in solutions while engulfing dissolved or dispersed compounds together in a dose-dependent manner and shows unique optical characteristics because the dendrimer products exhibit aggregation-induced emission. Furthermore, the emission of the dendrimer causes considerable fluorescence resonance energy transfer (FRET) to GFP derivatives upon association. We could easily monitor assemblies by FRET states and particle sizes and have confirmed a stable presence in the buffer for at least a month. Further tracking of nanocapsules by fluorescence confirmed efficient uptake into some cancer cells. Nanocapsules based on GFP variants with or without a cell-surface-specific tag demonstrated that the tag improved the potential for specific targeted delivery. There were also indications that the nanocapsules became unstable after cellular uptake in the intracellular environment. We report here the simple preparation of traceable, stable, and biocompatible self-assembled nanocapsules as the basis for a versatile drug delivery system.

Nanogel: A versatile drug delivery system for the treatment of various diseases and their future perspective.

Nanogel (NG) drug delivery systems have emerged as promising tools for targeted and controlled drug release, revolutionizing treatment approaches across various diseases.Their unique physicochemical properties, such as nano size, high surface area,biocompatibility, stability, and tunable drug release, make themideal carriers for a wide range of therapeutic agents. Nanogels (NGs), characterized by their 3D network of crosslinked polymers, offer unique edges like high drug loading capacity, controlled release, and targeted delivery. Additionally, the diverse applications of NGs in medical therapeutics highlight their versatility and potential impact on improving patient outcomes. Their application spans cancer treatment, infectious diseases, and chronic conditions, allowing for precise drug delivery to specific tissues or cells, minimizing side effects, and enhancing therapeutic efficacy. Despite their potential, challenges such as scalability, manufacturing reproducibility, and regulatory hurdles must be addressed. Achieving clinical translation requires overcoming these obstacles to ensure therapeutic payloads' safe and efficient delivery. Strategies such as surface modification and incorporating stimuli-responsive elements enhanced NG performance and addressed specific therapeutic challenges. Advances in nanotechnology, biomaterials, and targeted drug design offer opportunities to improve the performance of NGs and address current limitations. Tailoring NGs for exploring combination therapies and integrating diagnostics for real-time monitoring represent promising avenues for future research. In conclusion, NG drug delivery systems have demonstrated tremendous potential in diverse disease applications. Overcoming challenges and leveraging emerging technologies will pave the way for their widespread clinical implementation, ushering in a new era of precision medicine and improved patient care.

Polydopamine-Coated Zn-MOF-74 Nanocarriers: Versatile Drug Delivery Systems with Enhanced Biocompatibility and Cancer Therapeutic Efficacy

Polydopamine-Coated Zn-MOF-74 Nanocarriers: Versatile Drug Delivery Systems with Enhanced Biocompatibility and Cancer Therapeutic Efficacy

Reciprocal Interaction with Neutrophils Facilitates Cutaneous Accumulation of Liposomes.

Liposomes are versatile drug delivery systems in clinical use for cancer and many other diseases. Unfortunately, PEGylated liposomal doxorubicin (sLip/DOX) exhibits serious dose-limiting cutaneous toxicities, which are closely related to the extravascular accumulation of sLip/DOX in the dermis. No clinical interventions have been proposed for cutaneous toxicities due to the elusive transport pathways. Herein, we showed that the reciprocal interaction between liposomes and neutrophils played pivotal roles in liposome extravasation into the dermis. Neutrophils captured liposomes via the complement receptor 3 (CD11b/CD18) recognizing the fragment of complement component C3 (iC3b) deposited on the liposomal surface. Uptake of liposomes also activated neutrophils to induce CD11b upregulation and enhanced the ability of neutrophils to migrate outside the capillaries. Furthermore, inhibition of complement activation either by CRIg-L-FH (a C3b/iC3b targeted complement inhibitor) or blocking the phosphate negative charge in mPEG-DSPE could significantly reduce liposome uptake by neutrophils and alleviate the cutaneous accumulation of liposomes. These results validated the liposome extravasation pathway mediated by neutrophils and provided potential solutions to the devastating cutaneous toxicities occurring during sLip/DOX treatment.

Rubber oily liquids as transdermal and periodontal pocket drug delivery systems

This study investigates the incorporation of block natural rubber (NR) as a viscosity-inducing agent in NR oily liquids designed for drug delivery systems. A variety of liquids, encompassing natural oils, synthetic and non-oil liquids, and a eutectic mixture, were incorporated with NR using solvent displacement technique. Successful formulations were achieved for several oily liquids, with viscosity correlating to NR concentration. Particularly, a eutectic mixture of menthol and camphor exhibited optimal viscosity by direct dissolving enabling the development of transdermal ibuprofen delivery and injectable azithromycin for periodontitis treatment. NR prolonged the release of both drugs. The extended-release ibuprofen system holds promise for transdermal applications, while the azithromycin system displayed inhibitory effects against Staphylococcus aureus, Streptococcus mutans, and Porphyromonas gingivalis, suggesting potential for periodontitis treatment. Overall, this investigation advances the development of NR oily liquids as a versatile drug delivery system that can be applied both on the skin and for the local injection into the periodontal pocket, showcasing promise for various therapeutic applications.

Injectable hydrogel based on liposome self-assembly for controlled release of small hydrophilic molecules

Controlled release of low molecular weight hydrophilic drugs, administered locally, allows maintenance of high concentrations at the target site, reduces systemic side effects, and improves patient compliance. Injectable hydrogels are commonly used as a vehicle. However, slow release of low molecular weight hydrophilic drugs is very difficult to achieve, mainly due to a rapid diffusion of the drug out of the drug delivery system. Here we present an injectable and self-healing hydrogel based entirely on the self-assembly of liposomes. Gelation of liposomes, without damaging their structural integrity, was induced by modifying the cholesterol content and surface charge. The small hydrophilic molecule, sodium fluorescein, was loaded either within the extra-liposomal space or encapsulated into the aqueous cores of the liposomes. This encapsulation strategy enabled the achievement of controlled and adjustable release profiles, dependent on the mechanical strength of the gel. The hydrogel had a high mechanical strength, minimal swelling, and slow degradation. The liposome-based hydrogel had prolonged mechanical stability in vivo with benign tissue reaction. This work presents a new class of injectable hydrogel that holds promise as a versatile drug delivery system. Statement of significanceThe porous nature of hydrogels poses a challenge for delivering small hydrophilic drug, often resulting in initial burst release and shorten duration of release. This issue is particularly pronounced with physically crosslinked hydrogels, since their matrix can swell and dissipate rapidly, but even in cases where the polymers in the hydrogel are covalently cross-linked, small molecules can be rapidly released through its porous mesh. Here we present an injectable self-healing hydrogel based entirely on the self-assembly of liposomes. Small hydrophilic molecules were entrapped inside the extra-liposomal space or loaded into the aqueous cores of the liposomes, allowing controlled and tunable release profiles.

Ufosomes as Topical/Transdermal Drug Delivery System: Structural Components, Preparation Techniques and Therapeutic Application.

Fatty acid vesicles, or ufasomes, are spherical structures that encapsulate and deliver bioactive molecules to the skin or other tissues. They are formed from both saturated and unsaturated fatty acids and offer advantages over liposomes, including greater stability and a wider range of pH compatibility. They are composed of two layers of fatty acid molecules with their hydrocarbon tails facing inwards and their carboxylic groups facing outwards. The space between the two layers is filled with surfactants. There are various methods for characterizing and evaluating the properties of vesicles and drug-loaded vesicles, such as differential scanning calorimetry (DSC), Electron microscopy, UV-visible spectrophotometry, Dialysis, Franz diffusion cell, and stability testing. Each method provides specific information about the vesicles, such as their size, zeta potential, morphology, drug content, entrapment efficiency, drug release, permeability, and stability. Ufasomes have potential applications in topical/transdermal drug delivery as food additives, cosmetics, vaccines, gene therapy vectors, and diagnostic tools. Their ability to encapsulate and deliver bioactive molecules makes them valuable in various fields, including drug delivery and biomedical research. In summary, fatty acid vesicles represent a versatile drug delivery system with potential applications in various fields.

Hollow-structured covalent organic framework decorated with FA-PEG: A biocompatible nanocarrier for targeted and pH-responsive release of doxorubicin

Hollow nanostructures hold great promise for drug delivery applications due to their considerable capabilities for efficient drug encapsulation alongside distinct physicochemical attributes. Herein, an imine-linked hollow nanosphere covalent organic framework (COF) with high surface area and well-structured porosity was developed serving as a versatile drug delivery system (DDS) to achieve targeted and effective delivery of doxorubicin (DOX) as a chemotherapeutic agent. The production of COF hollow nanoparticles included the use of a heterogeneous nucleation and growth method, followed by the subsequent encapsulation of DOX. Following this, the nanoparticles underwent functionalization with folate-poly (ethylene glycol)-amine (FA-PEG) using a bonding defect strategy. An in vitro cytotoxicity assay and flow cytometry study against FR-negative HEK293 and FR-positive MCF7 cells were performed, revealing that FA-PEG-functionalized HCOF exhibited a unique targeting effect on cancer cells, surpassing the impact of DOX@HCOF on FR-positive MCF7 cancer cells. Additionally, the hollow architecture of the COF is engineered to undergo disintegration selectively under conditions of cancer cell pH, facilitating the comprehensive release of DOX. The pH-responsive and tumor-targeted attributes of the DOX@HCOF-PEG-FA open new avenues for incorporating structural engineered HCOFs as a promising drug carrier capable of regulating drug release and augmenting therapeutic efficacy.

Bilosomes as a Versatile Drug Delivery System: Preparation Techniques and Biomedical Application

Bilosomes as a Versatile Drug Delivery System: Preparation Techniques and Biomedical Application

The Effect of Cholesterol Content on the Adjuvant Activity of Nucleic-Acid-Free Lipid Nanoparticles.

RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response. However, the properties of LNPs that contribute to their adjuvant activity continue to require clarification. To characterize the relationships between the lipid composition, particle morphology, and adjuvant activity of LNPs, the nanostructures of LNPs and their antibody production were evaluated. To simply compare the adjuvant activity of LNPs, empty LNPs were subcutaneously injected with recombinant proteins. Consistent with previous research, the presence of ionizable lipids was one of the determinant factors. Adjuvant activity was induced when a tiny cholesterol assembly (cholesterol-induced phase, ChiP) was formed according to the amount of cholesterol present. Moreover, adjuvant activity was diminished when the content of cholesterol was excessive. Thus, it is plausible that an intermediate structure of cholesterol (not in a crystalline-like state) in an intra-particle space could be closely related to the immunogenicity of LNPs.

Insights into Translational and Biomedical Applications of Hydrogels as Versatile Drug Delivery Systems.

Hydrogels are a network of crosslinked polymers which can hold a huge amount of water in their matrix. These might be soft, flexible, and porous resembling living tissues. The incorporation of different biocompatible materials and nanostructures into the hydrogels has led to emergence of multifunctional hydrogels with advanced properties. There are broad applications of hydrogels such as tissue culture, drug delivery, tissue engineering, implantation, water purification, and dressings. Besides these, it can be utilized in the field of medical surgery, in biosensors, targeted drug delivery, and drug release. Similarly, hyaluronic acid hydrogels have vast applications in biomedicines such as cell delivery, drug delivery, molecule delivery, micropatterning in cellular biology for tissue engineering, diagnosis and screening of diseases, tissue repair and stem cell microencapsulation in case of inflammation, angiogenesis, and other biological developmental processes. The properties like swellability, de-swellability, biodegradability, biocompatibility, and inert nature of the hydrogels in contact with body fluids, blood, and tissues make its tremendous application in the field of modern biomedicines nowadays. Various modifications in hydrogel formulations have widened their therapeutic applicability. These include 3D printing, conjugation, thiolation, multiple anchoring, and reduction. Various hydrogel formulations are also capable of dual drug delivery, dental surgery, medicinal implants, bone diseases, and gene and stem cells delivery. The presented review summarizes the unique properties of hydrogels along with their methods of preparation and significant biomedical applications as well as different types of commercial products available in the market and the regulatory guidance.

Lipoprotein-mimicking nanotherapeutics reconstituted with chenodeoxycholic acid modified protein for efficient tumor targeting

Lipoprotein-derived nanotherapeutics based on endogenous lipid supramolecules have been regarded as an exceptional and promising approach for anti-tumor drug delivery. However, certain challenges associated with the main component apolipoprotein, such as limited availability, high cost, and insufficient specificity of relevant receptor expression, pose significant barriers to its widespread development and application. The objective of this study is to fabricate lipoprotein-mimicking nanocomposites, denoted as CA-P-rHDL by substituting apolipoprotein with chenodeoxycholic acid (CA) modified bovine serum albumin (BSA), and subsequently assess their tumor-targeting capability and anti-tumor efficacy. CA modified BSA (CA-BSA) was successfully synthesized and characterized by quantifying the degree of protein substitution. Subsequently, a nanostructured lipid carrier (NLC) mimicking the hydrophobic core of natural lipoproteins was attached with CA-BSA to form a lipoprotein-mimic nanocomplex termed as CA-rHDL. CA-rHDL was endowed with lipoprotein-like structures, favorable particle size, zeta potential and excellent paclitaxel encapsulation (termed as CA-P-rHDL). The internalization of CA-rHDL by HepG2 cells exhibited significantly superior efficiency, with a notably higher in HepG2 cells compared to LO2 cells. Confocal laser scanning microscopy revealed that CA-rHDL evaded lysosomal degradation and was evenly distributed throughout the cells. CCK-8 studies demonstrated that CA-P-rHDL exhibited significantly superior inhibition of tumor cells growth compared to other paclitaxel formulations in vitro. Moreover, in vivo imaging observation in H22 tumor-bearing mouse models exhibited a rapid and consistent accumulation of CA-rHDL within tumors, while CA-P-rHDL demonstrated remarkable efficacy against cancer in these mice. These exceptional capabilities of CA-P-rHDL can be attributed to the synergistic targeting effect facilitated by the combination of CA and BSA, rendering it a promising and versatile drug delivery system for targeted anticancer therapy. Consequently, CA-P-rHDL established a highly potential platform for simulating the reconstitution of supramolecular nanovehicles.

Lipid nanoparticles for enhancing oral bioavailability.

In recent studies, lipid nanoparticles have attracted attention as drug delivery systems owing to their preeminent potential in achieving the desired bioavailability of biopharmaceutics (BCS) class II and class IV drugs. The current debate concerns the bioavailability of these poorly absorbed drugs with their simultaneous oral degradation. Lipid nanoparticles, including solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), are lipid-based carrier systems that can effectively encapsulate both lipophilic and hydrophilic drugs, offering versatile drug delivery systems. The unique properties of lipids (biodegradability and biocompatibility) and their transportation pathways enhance the biological availability of drugs. These particles can increase the gastrointestinal absorption and solubilization of minimally bioavailable drugs via a selective lymphatic pathway. This review mainly focuses on providing a brief update on lipid nanoparticles (LNPs) that synergistically increase the bioavailability of limited permeable drugs and highlight the transversal mechanisms of LNPs across the gastrointestinal hurdles, transmembrane absorption, transport kinetics, and computational tools. Finally, the present hurdles and future perspectives of LNPs for oral drug delivery systems are discussed.

A Review on Oleogels and its Role in Pharmaceutical Field

Gel-based products called oleogels due to their required rheological, physical, and chemical stabilities in semisolid formulations not only have wide applications in the cosmetic industry, and nutraceutical industries but also they are used largely in various pharmaceutical field for formulating various topical drug delivery system and also as oil-based gels as versatile drug delivery systems for paediatric purpose. Oleogels are semisolid non-crystalline, thermo-reversible viscoelastic systems which consist of a lipophilic liquid phase (mineral or vegetable oils, isopropyl myristate) gelled with a suitable gelling agent referred as organogelators which can improve drug penetration through the stratum corneum because of their lipophilic nature. The polar phase gets trapped inside the three-dimensional networked structure present in the oleogels system, which is formed due to physical interactions among the self-assembled structures of organogelators. As these systems are resistant to the effects of moisture and do not require the addition of stabilizers or preservatives and hence they are preferred in drug delivery systems over conventional gels. The present article focuses on components, formulation aspects, and recent role of oleogels products showing its pharmaceutical applications.

Zeolitic imidazole framework-8 loaded gelatin methacryloyl microneedles: A transdural and controlled-release drug delivery system attenuates neuroinflammation after spinal cord injury

Spinal cord injury (SCI) is a matter of significant clinical concern, often treated through early surgical decompression along with methylprednisolone sodium succinate (MPSS). However, the side effects and the unsatisfactory focal concentration of MPSS have limited its further applications. To address this limitation, herein, a versatile drug delivery system of zeolitic imidazole framework-8 (ZIF-8) and gelatin methacryloyl microneedles (GelMA MNs) was developed for stable, transdural, and controlled sustained release of drugs in SCI. The microneedles were used to create tiny pores in the dura mater, allowing for the direct administration of drugs into the spinal cord. ZIF-8 provided a secondary extended release once they were separated from the microneedles. To attenuate the neuroinflammation, MPSS was selected. Such a combination of ZIF-8 and GelMA MNs was able to prolong the release period of MPSS to five days. The system showed transdural capacity, reduction of M1 polarization, and decrease in NLRP3-positive inflammasome and proinflammatory cytokines. In vivo studies indicated that this novel drug delivery strategy could constrict the inflammatory microenvironment, reduce glial scar formation, and promote neural regeneration. Thus, this versatile drug delivery system provides an up-and-coming alternative for stable, transdural, and controlled sustained release of drugs to those suffering from SCI.

Electrospun Core-Sheath Nanofibers with a Cellulose Acetate Coating for the Synergistic Release of Zinc Ion and Drugs.

Precisely modulating the synergistic release behavior of multiple bioactive substances has emerged as a formidable challenge in recent years. In this work, we successfully prepared core-sheath nanofibers, where a thin cellulose acetate (CA) coating enrobed the core. Curcumin (Cur) was encapsulated in the core layer as a model drug, while zinc oxide (ZnO) nanoparticles were loaded on the sheath layer. The prepared fiber exhibited a straight cylindrical morphology containing nanoparticles, and the distinct core-sheath nanostructure was demonstrated through transmission electron microscopy (TEM). X-ray diffraction (XRD) and Fourier transform infrared (FTIR) were conducted to study the physical state and compatibility among CA, Cur, and ZnO. Drug release data indicated that core-sheath nanofibers were able to decelerate the rate of drug release, and the thickness of the sheath layer increased in the presence of ZnO particles. Most remarkably, these core-sheath nanofibers exhibited the remarkable ability to sustain the release of drugs and zinc ion (Zn2+), the two-day synergistically release behavior leading to a significant increase in cell proliferation. This material preparation strategy for the synergistic and controlled release of two bioactive substances is instructive for the exploration of innovative and versatile drug delivery systems.

Electrosprayed Poly-butyl-succinate microparticles for sustained release of Ciprofloxacin as an antimicrobial delivery system

The increasingly complex treatment of bacterial infections, and its relevance in the clinical setting, requires the development of innovative strategies to improve patients' quality of life. In this context, polymeric microparticles represents a versatile drug delivery system (DDS) capable of improving the antibiotics' efficacy in the treatments, by loading drugs while modifying their release profile. In this study we aimed to produce polymeric microparticles by electrospraying using Poly-Butyl-Succinate (PBS), a biodegradable and biocompatible polyester. This versatile and easy-to-use technique enabled the incorporation of the poorly water-soluble Ciprofloxacin (CPX) into the polymer matrix. CPX is a fluoroquinolone antibiotic, inhibiting bacterial replication and effectively treating various infections. PBS is a well-known water-insoluble polymer with tuneable chemical-physical properties, also used for tissue regeneration and wound healing applications. An ex-vivo permeation study on porcine skin, serving as a model for human skin, was performed to assess potential enhancement in drug permeation. The microparticles were characterized by means of different techniques (SEM-EDX, XRD, ATR-FTIR, DSC), and their degradation rate was tested in DPBS and human plasma. Moreover, the as-produced DDS enabled the sustained release of CPX for several days, which proved effective against S. aureus and P. aeruginosa and also against a reference group of bacteria of skin microbiota often involved in pathological processes that make wounds chronic and difficult to heal. MIC and MBC assays were conducted using different culture media. Effective antibacterial activity was observed, along with inhibition of P. aeruginosa biofilm formation at sub-MIC concentrations.

A Comprehensive Review on Recent Advances and Patents of Niosomes

Abstract: Niosomes are novel, self-assembled vesicular carriers that deliver both lipophilic and hydrophilic drugs at the specific site in a targeted way, enhancing bioavailability and extending therapeutic effects. Niosomes are a versatile drug delivery system with a diverse range of applications from gene to brain-targeted delivery and they are more attractive choices than liposomes as they are efficient at biodegrading. Niosome offers several advantages over conventional drug delivery systems, including enhanced stability, and also have gained a lot of focus in natural product delivery in recent years. This review provides a comprehensive view of niosomal research and recent advancements, including classification and fabrication methods, and their role in drug delivery and targeting. The description of the rise in niosomal formulation patents around the world is also elaborated along with the natural product delivery of niosomes which has recently gained significance. Patents on novel preparation, loading, and modification techniques have enhanced the importance of niosome in the pharmaceutical industry.

Thermo-responsive Diels-Alder stabilized hydrogels for ocular drug delivery of a corticosteroid and an anti-VEGF fab fragment

In the present study, a novel in situ forming thermosensitive hydrogel system was investigated as a versatile drug delivery system for ocular therapy. For this purpose, two thermosensitive ABA triblock copolymers bearing either furan or maleimide moieties were synthesized, named respectively poly(NIPAM-co-HEA/Furan)-PEG6K-P(NIPAM-co-HEA/Furan) (PNF) and poly(NIPAM-co-HEA/Maleimide)-PEG6K-P(NIPAM-co-HEA/−Maleimide) (PNM). Hydrogels were obtained upon mixing aqueous PNF and PNM solutions followed by incubation at 37 °C. The hydrogel undergoes an immediate (<1 min) sol-gel transition at 37 °C. In situ hydrogel formation at 37 °C was also observed after intravitreal injection of the formulation into an ex vivo rabbit eye. The hydrogel network formation was due to physical self-assembly of the PNIPAM blocks and a catalyst-free furan-maleimide Diels−Alder (DA) chemical crosslinking in the hydrophobic domains of the polymer network. Rheological studies demonstrated sol-gel transition at 23 °C, and DA crosslinks were formed in time within 60 min by increasing the temperature from 4 to 37 °C. When incubated at 37 °C, these hydrogels were stable for at least one year in phosphate buffer of pH 7.4. However, the gels degraded at basic pH 10 and 11 after 13 and 3 days, respectively, due to hydrolysis of ester bonds in the crosslinks of the hydrogel network. The hydrogel was loaded with an anti-VEGF antibody fragment (FAB; 48.4 kDa) or with corticosteroid dexamethasone (dex) by dissolving (FAB) or dispersing (DEX) in the hydrogel precursor solution. The FAB fragment in unmodified form was quantitatively released over 13 days after an initial burst release of 46, 45 and 28 % of the loading for the 5, 10 and 20 wt% hydrogel, respectively, due to gel dehydration during formation. The low molecular weight drug dexamethasone was almost quantitively released in 35 days. The slower release of dexamethasone compared to the FAB fragment can likely be explained by the solubilization of this hydrophobic drug in the hydrophobic domains of the gel. The thermosensitive gels showed good cytocompatibility when brought in contact with macrophage-like mural cells (RAW 264.7) and human retinal pigment epithelium-derived (ARPE-19) cells. This study demonstrates that PNF-PNM thermogel may be a suitable formulation for sustained release of bioactive agents into the eye for treating posterior segment eye diseases.