Polyurethanes (PUs) are versatile polymers comprising diisocyanates and polyol components and are known for their extinsive applications due to their flexibility, durability, and resilience (Liu H. et al., 2022; Peyrton and Avérous, 2021). PUs can exist in various forms, like flexible foams, rigid insulation, coatings, adhesives, and sealants. PUs boast diverse biomedical uses owing to their adaptable, biocompatible, and resilient nature. Their flexibility makes them ideal for catheters and tubing, lessening the risk of adverse bodily reactions and minimizing tissue damage during insertion (Wendels and Avérous, 2021; Feldman, 2021). Moreover, in crucial medical devices like pacemaker leads and artificial heart components, the durability of PUs and resistance to bodily fluids prevent degradation or adverse responses (Pfensig et al., 2022). PUs films serve as effective wound dressings, creating a barrier against bacteria while enabling oxygen and moisture passage, fostering an optimal environment for wound healing (Morales-González et al., 2022). Their customizability aids tissue engineering by mimicking natural tissue mechanics, supporting cell growth and regeneration within scaffolds (Naureen et al., 2021; Pedersen et al., 2022). Additionally, their lightweight quality, durability, and moldability provide comfort and functionality in prosthetic limbs, braces, and orthotic devices (Naureen et al., 2021). The capacity of PUs to encapsulate drugs and offer gradual release in drug delivery systems, as seen in controlled-release matrices or implant coatings, further demonstrates their versatility ( Scheme 1 ). (Laurano et al., 2021)

PUs have been utilized in various pharmaceutical formulations as more and more monomers became available. Recent literature and reviews mainly focus on the potential of PUs in drug delivery systems with emphasis on general properties and drug administration studies (Gupta, 2023; Nadaf et al., 2023). The drug delivery systems based on PUs exhibit noteworthy promise owing to their straightforward preparation, elevated pharmacological effectiveness, minimal toxicity, and precise control over drug release. Their responsiveness to stimuli, stability over time, and ability to solubilize hydrophobic drugs offer encouraging opportunities for advancing effective therapies within the realm of pharmaceuticals. Here we review the role of segmental structures and properties modulations in designing state-of-the-art polyurethanes for drug delivery systems (DDSs).

Drug delivery systems (DDSs) are natural, synthetic, or semi-synthetic materials that intermingle with living systems to cope with direct medical treatment and diagnostics (Abbasnezhad et al., 2021). The materials may be biodegradable, bioresorbable, biocompatible, and hemocompatible to perform their function according to the response of the host (Zhang S. et al., 2021). These materials can be divided into composites, polymers, carbon materials, and ceramics. Polyurethanes are one of the most promising and versatile materials, having a segmental block structure with fascinating features like tunable biological, mechanical, physiochemical, and tissue-compatible properties (Yang et al., 2021). The high elasticity and low glass transition temperature (Tg) due to soft segmental structures and high strength, Tg, and melting temperature (Tm) due to hard segments of PUs are unique physiochemical properties in the context of DDSs (Figure 1). (Shoaib et al., 2017a; De Souza et al., 2021)

PUs, due to their adaptable properties and widespread application in medicine, stand out as excellent options for delivering drugs. Their versatility has sparked considerable interest in the biomedical sector, where these have been extensively used in various forms—such as bulk devices, coatings, particles, and micelles—for drug delivery purposes. PUs have found roles in delivering antibiotics, anti-cancer medications, drug-eluting stents, dermal treatments, and intravaginal rings. To ensure the intended therapeutic impact, it is crucial to manage how PUs release drugs, controlling both the pace and duration. (Ghasemi and Ghezelsofloo). There are already commercially available PU-conjugated DDSs, like the Ornibel intravaginal ring, showcasing the adaptability of PU formation, allowing scientists to adjust the properties of the polymer to attain specific drug release patterns (Rajan et al., 2017). PU nanoparticles are the most promising DDS among all the other PU-related DDSs because of greater surface area, high drug distribution, enhanced selectivity, and increased drug-delivering efficacy. PU nanoparticle DDSs are extensively employed as the most efficient drug delivery carriers for stimuli-responsive drug delivery. In this review, the preparation and the physiochemical properties of PU nanoparticles for the use of drug delivery will be discussed. We will also discuss how the efficiency of DDSs depends on the structure of PU nanoparticles. This review also demonstrates the use of state-of-the-art PU nanoparticles in DDSs. The use of developed PU nanoparticle DDSs to treat various diseases will also be discussed.

Polymeric nanoparticles have become a potent tool for delivering drugs and diagnosis in the past few decades (Mishra et al., 2013). Typically characterized as compact colloidal substances consisting of macromolecular or molecular assemblies spanning a diameter of 1–500 nm, nanoparticles possess unique features such as elevated kinetic stability, diverse structural variations, rigid morphology, the capacity to integrate a variety of hydrophilic or hydrophobic medications, and numerous possibilities for functionalization (Rao, 2011; Morral-Ruíz and Melgar-Lesmes, 2016). Polymeric nanoparticles show potential as a therapeutic approach in the creation of nanostructured materials for drug delivery due to the mentioned characteristics. In this context, the crucial steps involve the careful selection of suitable polymers and their proper formulation to achieve the desired properties. Polyurethanes are particularly captivating in this regard, given their noteworthy attributes, including robust mechanical strength, biodegradability, biocompatibility, and versatile synthetic capabilities (Morral-Ruíz et al., 2016).

Polymeric nanoparticles can be easily crafted either by utilizing polymers which are preformed or through the polymerization of monomers directly by employing conventional polymerization or multiple reactions. Techniques like evaporation of the solvent, dialysis, salting-out, and supercritical fluid technology, which involves the rapid increase in the volume of a supercritical solution or its quick conversion into a liquid solvent, can be employed for preparing polymeric nanoparticles from already synthesized polymers. PU nanoparticles are conventionally synthesized from diisocyanates and diols/polyols or diamines through polycondensation or polyaddition reactions. PU nanoparticles can also be prepared directly by polymerization of monomers by using different emulsion techniques such as mini-emulsion, micro-emulsion, surfactant-free emulsion, and interfacial polymerization. These methods facilitate the integration of cell-penetrating molecules, stimuli-responsive linkages, and targeting ligands into the core PU structure. Additionally, they enable the design of nanoassemblies as nanovectors for drug delivery applications (Xu et al., 2010; Wang et al., 2013a).

In addition to the traditional polycondensation or polyaddition reactions involving diisocyanates and diols/polyols or diamines, PUs can engage in reactions with preformed synthetic polymers like poly ε-caprolactone or polysaccharides. This approach aims to achieve polymers that are more biocompatible and biodegradable. Conversely, interfacial polymerization at the interface of two immiscible liquids results in the creation of functionalized structures. These structures exhibit multimodal distributions with varying sizes and the coexistence of monomers, empty micelles, microemulsion droplets, and nanoemulsions. The microemulsion droplets and nanoemulsions serve as templates and micro-nano-reactors for the synthesis of PU nanoparticles (Borcan et al., 2023). Several techniques such as emulsion/solvent evaporation and nanoprecipitation/solvent evaporation have been employed for the formation of PU nanoparticles from already synthesized polymers. The synthesis of PU nanoparticles from polymerization and prepolymers is demonstrated in Scheme 2. Additionally, desolvation, dialysis, ionic gelation, nanoprecipitation, solvent evaporation, salting out, spray drying and supercritical fluid methods are utilized for polymeric nanoparticles synthesis. However, the choice of an appropriate method depends upon various factors.

The efficiency of the DDSs can be significantly enhanced by employing them in the form of nanoparticle systems because of their better water solubility, drug distribution, biocompatibility, and targeting ability (Pabari et al., 2021). Polyurethane nanoparticles are tiny particles made of polyurethane employed in DDSs due to their unique properties that make them suitable for transporting drugs to specific bodily targets. PU nanoparticles have the ability to encapsulate drugs within their structure. This encapsulation protects the drug from degradation and ensures controlled release at the targeted site. The engineered nanoparticles can be specific in targeting body cells or tissues. Functionalization with ligands or antibodies allows them to recognize and bind to specific receptors on cell surfaces, enhancing their specificity (Omrani et al., 2017; Shoaib et al., 2018). The production of PUs involve a wide variety of materials including the use of a monomer, or a low-molecular-weight pre-polymer solvent. The creation of the carbamate (urethane) linkage is a representation of the outcomes of the primary processes in PU synthesis. Their properties are dependent on the incorporation of different groups like ester, ether, urea, aromatic, carbodiimides in the polymeric structures. The molecular structure, rigidity, and flexibility control the overall PU systems and their applications.

Moreover, their small size (usually 10–100 nm) enables easy transport through biological barriers and enhances their blood circulation time. Additionally, their stability helps in preserving the integrity of the drug until it reaches the desired location. PU nanoparticles offer controlled and sustained release of drugs. By modifying the structure of nanoparticles, the rate of drug release can be tailored to ensure a prolonged therapeutic effect and reduce the frequency of drug administration. PUs are often biocompatible which can be well-tolerated by the body, reducing the risk of adverse reactions when used as a drug carrier. Overall, PU nanoparticles offer a promising avenue for improving DDSs by enhancing drug stability, targeting specific cells or tissues, and providing controlled release kinetics, ultimately increasing the therapeutic effectiveness of various medications (Wang et al., 2013b).

For example, PUs designed for complete degradation triggered by intracellular GSH and acidic environments have been overlooked in targeted controlled drug delivery. To address this, novel waterborne polyurethane (WPU) nanoparticles capable of breaking down in response to GSH and acid were explicitly developed for delivering the lipophilic anti-cancer drug doxorubicin (DOX) (Iyer et al., 2020b). These resulting PUs spontaneously form nanoparticles in water, as observed through DLS and SEM, demonstrating rapid inflammation and disintegration in an environment mimicking intracellular reduction and acidity. In vitro release experiments revealed that in 10 mM GSH at pH 6, 74% of the loaded with DOX was released from these WPU nanoparticles within 24 h. MTT assay results indicated that the cytotoxicity of DOX-loaded WPU nanoparticles against A375 human malignant melanoma cells was comparable to free DOX, while blank WPU nanoparticles exhibited low cytotoxicity. These findings highlight the potential of GSH and acid-responsive WPU nanoparticles as effective carriers for intracellular drug delivery, responsive to both pH levels and redox conditions. Moreover, the PU DDSs can also act as activatable DDSs when coated with some targeting agents according to the requirement. The activatable PU DDSs can be the most advanced delivery system in treating various diseases, including cancer (Zanetti-Ramos et al., 2009; Wang et al., 2013b).

Polymeric nanomicelles DDSs with acid-sensitive charge-reversal properties in response to the acidic tumor microenvironment, facilitating their entry into cancer cells have been the focus of many studies. For instance, Liu et al. utilized carboxyl groups and tertiary amine groups to synthesize amphiphilic PUs containing carboxylic groups (PUC) and amine groups (PUN). The stability and cellular studies conducted indicated that PUC-PUN micelles displayed remarkable stability under simulated normal physiological conditions and significantly enhanced cellular uptake efficiency. These micelles exhibited minimal cytotoxicity against SGC-7901 and MGC-803 cells, while PUC-PUN/DOX micelles showed increased cytotoxicity compared to both pure DOX and PUN/DOX micelles. Moreover, in vivo experiments assessing antitumor activity revealed that PUC-PUN/DOX micelles demonstrated superior tumor inhibition efficacy and safety when compared to pure DOX. The study highlights that charge reversal is a potential strategy for designing efficient DDSs (Liu J. et al., 2022). He, Wanying, et al. prepared pH responsive PUs containing methoxyl-poly (ethylene glycol) (mPEG), carboxylic acid groups, and piperazine groups as charge reversal intelligent intracellular drug delivery carriers. They found that the charge-reversal property of the prepared PU can improve the cellular uptake behavior and intra-cellular drug release in both HeLa cells and MCF-7 cells (Figure 3). (He et al., 2016)

Furthermore, Cao et al. synthesized PU-based nanoparticles loaded with a drug known as fenofibrate (FNB-PU) to demonstrate the in vitro and in vivo efficacy of the drug for the treatment of nonalcoholic fatty liver disease. They prepared PU nanoparticles by a green process, and FNB was encapsulated into the PU nanoparticles by a facile sonication method. The low molecular weight of the single chain which is about 197 kDa and the weight of each nanoparticle determined by single-angle scattering data was approximately in the range of 6 - 8 × 10 ⁶. It means that each nanoparticle contained 300–400 molecules having a tight and compact structure with 39 nm in size. When loaded with the drug, the size of the FNB-PU was about 57.7 nm. The enlargement in the size of PU nanoparticles demonstrated successful encapsulation of FNB with PU nanoparticles. The FNB-PU displayed two modes of drug release in the in vitro system, initial burst of drug release and subsequent slower drug release. The encapsulation of FNB into the PU nanoparticles increased the drug release by about 2.8 folds to the FNB aqueous suspension. Finally, the FNB-PU was orally administrated to a mouse model suffering from nonalcoholic fatty liver to check the in vivo efficacy of the drug release. The in vivo results demonstrated 8.87 folds increase in the drug release in the case of FNB-PU as compared to crude FNB. The enhancement in the drug release mentioned in the literature was because of the endocytosis of anionic PU micelles (Figure 4). (Cao et al., 2018)

Essentially, understanding how drugs are released from polymers often involves analyzing the process through a mass transport perspective, commonly employing Fick’s law of diffusion for modeling. Typically, the drug is either dispersed throughout the polymer structure or encapsulated within it. For systems where the drug is delivered as an encapsulated payload or at concentrations below a critical level, various mass transport phenomena govern the delivery process: the drug must 1) dissolve into the polymer; 2) diffuse through it; 3) pass through a layer of stagnant liquid; and 4) convective transfer into the surrounding environment. When the drug concentration is exceeded, it still proceeds via these transport pathways but can now diffuse through channels that are plentiful in the drug in the material. Moreover, the polymer characteristics, including swelling, erosion, and degradation rate, can affect how quickly drugs are delivered. Additionally, different covalent and non-covalent interactions are involved in drug formulations and release. The way that pharmaceuticals are released over time can also be changed by more advanced methods including covalently attaching the drug to the polymer, using materials that respond to stimuli, or adding pore formers into the formulation (Allami et al., 2021).

Lately, there has been notable attention focused on the advancement of fluorescent polymers due to their inherent benefits, such as minimal toxicity, favorable biocompatibility, extended stability, and improved manufacturability (He et al., 2023; Ma et al., 2023). Specifically, fluorescent polyurethane (PU) stands out as a highly sought-after polymer due to its exceptional blend of distinctive characteristics, including remarkable mechanical durability, effective resistance to abrasion, and superior elasticity. Polyprodrugs have garnered considerable interest as nanomedicines, aiming to enhance drug loading capabilities and minimize toxicity associated with carriers. Polyurethane prodrug nanoparticles and micelles with a stimuli-responsive nature for imaging-guided therapy are gaining momentum as alternatives to non-assimilable zwitterionic materials prepared via living or free radical polymerization. These polymers undergo self-assembly to form vesicles and structures resembling nanotubes, demonstrating size expansion and contraction, metamorphosis, and changes in color mediated by hydrogen bonding. Furthermore, these polymeric structures exhibit extremely high stability and rapid responsiveness, enabling the creation of “on-off” switchable nanocarriers suitable for drug delivery and theranostic applications. Due to their inherent fluorescence, the uptake by cells and the release of drugs inside cells from PU nanoparticles can be conveniently monitored without the need for labeling (Figure 7). (Zhou et al., 2022a)

As an illustration, Qian et al. developed a pH-responsive zwitterionic polyurethane prodrug for improved cancer therapy through drug delivery. The augmented cytotoxicity mechanism of the polymer prodrug micelles was investigated over various durations using both flow cytometry and fluorescence microscopy. Findings revealed that the fluorescence intensity of the prodrug micelles surpassed that of PEG-based micelles at equivalent exposure periods, suggesting a more effective cellular uptake of the prodrug micelles (He Q. et al., 2021).

Polyurethane-centered drug delivery systems employing targeted distribution mechanisms present an innovative strategy within the pharmaceutical realm. These systems strive to amplify the effectiveness and precision of delivering medications to specific locations in the body, optimizing therapeutic impacts while mitigating potential side effects. Targeted polyurethane drug delivery involves crafting formulations capable of navigating physiological barriers and selectively releasing drugs precisely where intended (Wienen et al., 2023).

Polyurethane carriers can be engineered to transport drugs directly to target tissues or organs, elevating the overall treatment efficacy. By functionalizing polyurethane surfaces, it becomes possible to attach ligands or targeting components that interact with particular receptors at the designated site, refining the accuracy of drug delivery. Additionally, polyurethane drug delivery systems (PU DDSs) can be tailored to respond to specific stimuli like pH, temperature, or enzymatic activity, triggering drug release solely upon encountering the desired conditions. Leveraging polyurethane in nanoparticle form facilitates the creation of carriers boasting high surface areas, enhancing drug loading capacity and enabling precise delivery to specific cells or tissues (Tao et al., 2023). To meet these requirements, Song and colleagues devised an innovative polyurethane nanomicelle with targeting capabilities and tumor-degradable features for the versatile delivery of anticancer drugs. The polyurethane was created by synthesizing biodegradable poly (ε-caprolactone) (PCL) and l-lysine ethyl ester diisocyanate (LDI). It was then elongated using a newly designed l-cystine-derivatized chain extender containing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA). The polymer chain terminated with a detachable methoxyl-poly (ethylene glycol) incorporating a benzoic-imine linkage (BPEG) sensitive to pH variations. These resulting polymers demonstrated favorable self-assembly characteristics, responsiveness to stimuli, good compatibility with cells, and a high capacity for loading doxorubicin (DOX). Additionally, folic acid (FA) was effectively attached to the polyurethane micelles as a representative targeting agent using a click reaction. The inclusion of FA resulted in heightened cellular uptake and improved drug efficacy against FA-receptor-positive HeLa cancer cells in laboratory tests. This research serves as a demonstration of a straightforward strategy for designing externally triggered nanocarriers for targeted delivery to tumors and controlled release of drugs within cells (Figure 8). (Song et al., 2013)

Polyurethane-based drug delivery can serve in combined therapies, concurrently delivering multiple drugs to target different aspects of a disease or condition. The release pace of drugs within polyurethane systems can be finely adjusted, allowing for sustained or intermittent drug release as required for optimal therapeutic results. Furthermore, PU carriers can be integrated with imaging agents, enabling real-time tracking of drug dispersion and aiding in evaluating treatment effectiveness (Gajbhiye et al., 2020; Yang et al., 2020).

Activatable polyurethane drug delivery adheres to the principles of precision medicine, facilitating customized treatments based on individual patient needs and disease characteristics. Incorporating various activation methods or merging activatable polyurethane systems with other therapeutic approaches could offer versatile remedies for addressing intricate medical conditions. Furthermore, activatable systems that blend therapeutic and diagnostic functions (known as theranostics) can provide real-time monitoring of drug release and treatment effectiveness, contributing to more informed healthcare decisions. These systems contribute to the evolution of intelligent drug delivery platforms capable of adapting to changing physiological conditions, thereby improving therapeutic efficacy and minimizing side effects (Zhang and Pu, 2020).

The drug-delivering efficiency of the delivery system can be improved by the integration of a specific stimulus for the drug release. Athar et al. developed redox-responsive cleavable soyabean-coated polyurethane nanomicelles and polyurethane-hyaluronic acid nanomicelles. The prepared drug carriers exhibited controlled self-assembly, stimulus-responsive drug release, excellent biocompatibility and high loading capacity of doxorubicin. All these features are responsible for effective activatable drug delivery by the nanomicelles (Mahdieh et al., 2022). Moreover, for further enhancing the drug delivery efficiency of the polyurethane-based nanomicelles, the material should be amphiphilic. Yu et al. synthesized amphiphilic micelles of polyurethane combined with methacrylate polyethylene glycol (mPEG) by sulphur linkages through ring opening reaction used for hydrophobic anticancer drug delivery (Yu et al., 2020). Jinhai Xie et al. have designed diol monomers based on trimethyl-locked benzoquinone (TMBQ) amphiphilic PU (PEG-PTU-PEG). The synthesized A-B-A-type, enzyme-responsive functional block copolymer PEG-PTU-PEG successfully encapsulates doxorubicin (DOX) in nanomicelles through self-assembly (Figure 9). Drug release and micelle disintegration result from the NAD(P) H: quinone oxidoreductase 1 (NQO1) enzyme eliminating TMBQ by lactonization through two-electron reduction, upsetting the hydrophilic–hydrophobic equilibrium of the PU micelle structure (Xie et al., 2023).

The macromolecular drug delivery agents are not so efficient in drug delivery and are not so responsive to a specific stimulus. To solve this problem, Chen et al. synthesized unimolecular micelles for the drug delivery approach instead of supramolecular micelles. He utilized dendritic polymer micelles with a polar framework for chemotherapeutic drug delivery, which has proved to be more effective in pH-responsive drug delivery due to the protonation of the dendritic polymer. The efficiency of the drug delivery agent has been improved due to the simplified chemistry of the urethane. The unimolecular micelles have also been employed for controlled drug release during chemotherapy (Chen and Liu, 2022). The internal bodily stimuli are proved to be not so effective in the case of controlled drug delivery. To enhance the sensitivity of the controlled delivery system, Sun et al. developed a monodispersed light-responsive polyurethane delivery system. The monodispersed nanoparticles loaded with the drug undergo rapid degradation upon light irradiation. The degradation of the delivery system has been investigated by the DLS method. The monodispersed nanoparticles loaded with a model drug Nile Red when irradiated with UV light degraded rapidly releasing the drug that was detected by fluorescence spectroscopy (Figure 10). This light-responsive polyurethane drug delivery can be the most advanced drug delivery approach (Sun et al., 2019).

Zhou and colleagues investigated the efficacy of delivering polyurethane-polyurea nanocapsules (Puua-NCs) with a shell that undergoes pH-induced cationization and redox-triggered release to the vascular system. They integrated the fluorescent lipophilic dye DiI into Puua-NCs of various sizes and concentrations. Cellular uptake studies conducted on human aortic endothelial cells revealed a dose-dependent uptake of these Puua-NCs. In a mouse model of atherosclerosis, particularly apolipoprotein E-deficient mice fed a Western diet, the circulating Puua-NCs remained stable and accumulated in the aortic endothelium and lesions within 24 h post intravenous administration. Treatment with thiol-reducing and oxidizing agents disrupted the disulfide bonds on the surface of internalized nanocapsules, leading to their disassembly and the release of the encapsulated cargo within cells. Ultimately, the research suggests that Puua-NCs have the potential to function as a redox-controllable drug delivery system for cardiovascular purposes (Zhou et al., 2022b).

Continuous advancements in nanotechnology are pivotal in refining activatable polyurethane systems, enabling the creation of smaller, more efficient carriers with enhanced drug-loading capabilities. Activatable drug delivery systems hold promise for tackling diseases typically challenging to treat due to drug resistance or complex underlying conditions. Overcoming these hurdles and exploring these perspectives will be critical in advancing activatable polyurethane drug delivery and translating it into practical, impactful clinical applications. Collaborative endeavors among researchers, clinicians, and industry partners will be instrumental in surmounting obstacles and harnessing the full potential of this technology (Bil et al., 2020; Cheng et al., 2021).

AI algorithms streamline the analysis of extensive datasets concerning polyurethane properties, drug interactions, and patient reactions. This optimization process significantly expedites the creation of specialized drug delivery systems. By employing machine learning models (MLMs), it becomes possible to forecast how polyurethane drug delivery systems will behave within a living organism. This encompasses foreseeing drug release rates, spotting potential side effects, and enhancing the system’s design for better therapeutic results (Suwardi et al., 2022).

Furthermore, AI plays a pivotal role in tailoring drug delivery systems to individual patients based on their unique genetic makeup, metabolic processes, and disease profiles. This shift towards personalized medicine has the potential to enhance treatment effectiveness while minimizing adverse effects. ML algorithms can be utilized to develop intelligent polyurethane systems that adjust drug release rates in response to real-time changes in the body, thereby enhancing precision and efficacy in drug delivery (Pugar et al., 2022).

The contribution of AI extends to swiftly evaluating the compatibility of polyurethane materials by predicting immune responses or toxic reactions. This accelerates safety assessments and ensures the reliability of drug delivery systems. By amalgamating data from various sources such as molecular databases, clinical trials, and patient records, AI systems offer comprehensive decision-making support to researchers and healthcare professionals engaged in polyurethane drug delivery (McDonald et al., 2023).

AI-powered algorithms also automate the optimization of designs for polyurethane drug delivery systems, efficiently exploring a vast array of possibilities that might not be discernible through conventional methods. Real-time monitoring of patient responses and system performance is made feasible through AI, enabling machine learning models to analyze this data and prompt adaptive changes in drug delivery parameters for ongoing optimization during treatment. AI algorithms can identify patterns associated with drug resistance, aiding in the proactive design of polyurethane drug delivery systems to counteract or mitigate resistance mechanisms (Sagdic et al., 2022).

The integration of AI and ML into polyurethane drug delivery systems holds immense potential for advancing precision medicine, expediting drug development, and ultimately enhancing patient outcomes. This advancement necessitates collaboration across disciplines, robust validation procedures, and continuous regulatory oversight to ensure the responsible and ethical application of these technologies in healthcare (Zohuri and Behgounia, 2023). Utilizing AI in nanomedicine in a number of areas, including data collection, nanosystem setup and optimization (including physicochemical, pharmacological, and synthetic parameters), and the fate of nanomedicine in vivo ( Figure 11). (Mozafari et al., 2023)

The integration of AI and ML into PU DDSs represents a groundbreaking advancement in the field of pharmaceutical technology. These intelligent systems leverage AI algorithms to optimize drug release profiles, enhance targeting precision, and personalize therapeutic regimens. ML models analyze vast datasets to predict patient responses, enabling tailored drug delivery strategies that consider individual variations in metabolism and physiology. Additionally, AI algorithms can optimize the design and fabrication of polyurethane-based drug delivery platforms, ensuring efficient and controlled release kinetics. This integration not only improves the overall efficacy of drug delivery systems but also opens avenues for real-time monitoring and adaptive adjustments, thereby revolutionizing the way therapeutic agents are administered. The synergy between AI, ML, and PU DDSs holds immense promise for advancing precision medicine and improving patient outcomes in the realm of pharmaceuticals (He S. et al., 2021).

PU nanoparticles are emerging as the most advanced drug delivery agents in the medical realm. The efficiency and functionality of the PUs DDSs can further be enhanced by carefully integrating modern features and by controlling their structure and design. PUs DDSs can act as state-of-the-art drug delivery agents, but a lot of research and practical work is needed to bring PUs from laboratories to hospitals. The controlling design and structure of PUs for targeted drug delivery and activatable drug delivery is a very challenging task to be accomplished. AI and Machine Learning can also be used to design modern PU DDSs for different pathological conditions. If proper research work is done to meet all these projected features, PU DDSs can act as the most effective delivery system in the biomedical field.

Polyurethanes (PUs) are intriguing polymers with diverse properties that make them highly suitable for applications in drug delivery and various biomedical contexts. These applications encompass nanoparticulate systems, stimuli-responsive scaffolds, and imaging-guided therapy. While PUs are extensively investigated for diverse biomedical uses, it is imperative to evaluate their actual impact on the healthcare system critically. The pharmaceutical sector is experiencing a rapid surge in the development of PU-based drug delivery systems for treating different medical conditions. A novel approach to designing PU-based medication delivery systems is emerging, facilitated by the integration of perspectives from both synthetic and biological sciences.

The distinctive characteristics of materials based on PUs present new possibilities for addressing significant challenges in drug formulation and developing advanced drug delivery systems with innovative capabilities. Overcoming the issue of poor drug solubility in PU formulation involves depositing large amounts of drugs in the amorphous state onto the PU nanoparticles skeleton. The extensive surface area, coupled with compatibility with different solvent systems, facilitates interaction with the aqueous environment and promotes the diffusion of dissolved drugs. Water uptake performance of PU nanoparticulate systems in various pH media reveal that these exhibit a higher swelling capacity in acidic environments compared to neutral and alkaline media. Biodegradation experiments involving enzymatic and hydrolytic degradation with amino acids or biodegradable components indicate a higher biodegradation rate.

Alternatively, the release patterns of drugs from PU-based materials can be controlled using various methods, such as combining swellable/erodible skeleton components, adjusting the intensity of drug/skeleton interactions, coating with membrane-like substances, and incorporating stimuli-responsive components.

Current manufacturing protocols for PU materials allow for the utilization of nearly any organic or inorganic material as a skeleton component, adaptable to formulate drugs with diverse physicochemical features and stability. However, additional in vivo studies are necessary to address safety concerns related to the biomedical applications of PU materials. While existing literature on PU materials for drug delivery primarily focuses on bench-scale production, the growing interest in their pharmaceutical applications encourages experimentation on a pilot scale as an initial step toward industrial production. Subsequent efforts should concentrate on transforming drug-loaded PU-based materials into practical medicines, exploring possibilities such as tablets, capsules, ointments, inhalation powders, or injectable formulations. It is crucial to retain the unique properties of PU materials during this transformation process.