Introduction

The nanoparticle (NP) technology is rapidly advancing, offering innovative and effective treatments for various medical conditions such as cancer, inflammation, cardiovascular diseases, psoriasis, diabetes, bone regeneration, gene therapy etc. These nanoparticles (NPs) are designed to overcome challenges like poor selectivity, known targeting sites, and side effects on various body tissues. They also address the limitations of micron-size particles, including surface area, site specificity, retention at the targeting site, swelling behaviour, drug loading, and release behaviour. Nanogels (NGs) type of NPs have garnered significant attention over the past 20 years due to their bio-compatibility, biodegradability, versatility, and safety from leakage [1,2,3,4,5]. In addition to in-vitro and in-vivo tests, other methods like ex-vivo and in-silico testing are used to validate drug delivery systems [6]. With the wide range of nanosized materials involved in nanotechnology-developed drug delivery systems, each material exhibits unique properties dependent on its nano-size. These properties allow for enhanced intracellular drug delivery, subcellular targeting, and the capability to access previously inaccessible body areas [7].

NGs are typically 3-dimensional submicron-sized networks of hydrophilic polymers developed by chemical or physical cross-linking that exhibit the full range of characteristics of both NPs and hydrogels (HGs). Ionic interactions, hydrogen bonds, electrostatic interactions, and hydrophobic interactions are the main types of physical cross-linking [8, 9]. While some studies have shown that NGs as large as 1,000 nm are reasonable, others have found that those as small as 200 nm are ideal for use in the medical field [10]. NGs may absorb a considerable amount of water. NG cross-linking network may be used as a grid to contain the internal fluid system, while the absorbed water is used as a filtration medium for cargo diffusion. NGs with an unsuitable zeta potential help avoid immune phagocytosis and may resist the adsorption of negatively charged proteins [2, 11]. Considering their high-level performance in extending blood circulation and boosting healing effectiveness, several drug carriers, including liposomes, polymer vesicles, and micelles, have drawn broad interest in studying controlled drug delivery [12,13,14].

NGs have been extensively researched for integrating and releasing actions of bioactive substances such as proteins, vitamins, and drugs [15], DNA, antigens, oligonucleotides, genes, as well as inorganic molecules such as quantum dots, silver NPs, magnetic NPs [16]. NGs may be delivered using one of two methods: passive targeting or active targeting. In the case of passive targeting, the size, swelling, surface charge, and various physicochemical attributes of the NGs reveal drug release. Active targets involve conjugating NGs with particular scaffolds that selectively identify and bind with some over-expressed receptors at the target areas, like in tumours. This process causes conjugated NGs to accumulate at the target site [17], attaining more than 98% loading efficiency. Since NGs are HGs, their capacity to resemble tissue is another distinctive quality that distinguishes them because of the significant water content and the bio-compatible ingredients utilized. Such gel topically has a calming effect that is highly helpful in treating conditions like wounds [18].

Drug delivery system

Developing effective treatments and tackling disorders is a significant challenge for formulation nowadays. The existing drugs and active molecules are often effective mechanisms for treating specific disorders, but their efficacy is sometimes severely constrained by challenges in their delivery. To bring drugs and active molecules to the target sites where they will have the most incredible pharmacological effects, a process known as a drug delivery system has been developed [19]. One of these systems' significant benefits is the ability to regulate the rate, timing, and target site of a drug's delivery to a patient [20]. NPs are essential in drug delivery as well-synthesized nanocarriers can meet high drug-loading levels and regulate drug release [21]. Their nanostructures and functions may increase delivery processes such as selectivity, decreasing toxicity and side effects. Polymeric NPs are essential in this context since their structure provides good bio-compatibility and biodegradability and can be readily functionalized [22]. Furthermore, while dealing with suitably functionalized polymer chains, it is reasonable to modify factors such as mechanical qualities, composition, or degradation rate. In the interest of completeness, these formulations are expensive, restricting their use in clinical practice.

Controlled and targeted drug delivery system

Compared to traditional formulations, controlled and specifically designed drug delivery systems are intended to produce significant benefits. They are optimizing the drug release from the delivery system since the rate and duration of the procedure dramatically affect the therapy's efficacy [23]. Controlled drug delivery systems (CDDS) should avoid restrictions on drug concentration within the targeted therapeutic range. Actuality, the drug release profile of traditional drug delivery techniques, is characterized by a rapid decline below the lowest effective concentration, followed by an increase to a peak concentration over the maximum safe concentration. A correctly constructed CDDS ensures the drug's blood concentration profile stays within these limits [24]. However, controlled drug release is not enough if it fails to take place in the tissues that we wish to address; a targeted drug delivery system (TDDS) is a different approach that can preferentially access a specific target area, emphasizing therapeutic benefits and minimizing undesirable effects produced by the drug's interaction with various body tissues [25]. TDDS and CDDS provide the potential to utilize a smaller dose of the drug compared to conventional therapies, and the carrier's structure may keep the drug in-vivo, preventing early deprivation or quick breakdown [26].

NGs

NGs are promising for therapeutics, diagnostics, macromolecules, and other applications. NGs, primarily hydrophilic and with a large capacity for guest molecules, are highly bio-compatible and have significant benefits over other nanomaterials for biomedical applications. Due to their distinctive characteristics, including stimuli-responsive behaviour, softness, and swelling, NGs shield the cargo from deterioration and removal and actively engage in the delivery process to create a regulated, triggered reaction at the target region. [27]. NGs offered merits are as follows:

  • High water content makes materials more bio-compatible, which causes them to behave like actual tissue and elicit favourable immune reactions.

  • Nanocarriers are biodegradable, making them non-toxic.

  • Drug loading capacity is high.

  • Controlling drug release by adjusting crosslinking densities [28].

  • Resist entrapment by the reticuloendothelial system quickly [29].

  • Tiny size makes them better at permeating biological membranes.

  • Drugs and charged solutes that are both hydrophilic and hydrophobic may be included (Fig. 1) [30].

  • Superior transport qualities [31].

Fig. 1
figure 1

Macroscopic and microscopic view of NGs. The figure was developed using BioRender (www.biorender.com) (accessed 5 October 2023)

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Limitations of NGs

NGs provide many benefits but have specific vital points that sometimes prevent their application. The limits of NGs are listed below:

  1. (a)

    The solvent and surfactants must be removed entirely using expensive methods.

  2. (b)

    There may be residual residues of monomers or surfactants, which might be hazardous.

  3. (c)

    Variation in manufacturing, whereby the usual qualities of NGs are only attainable within a specific range of dimensions [32].

Types of NGs

A cross-linked HG particle with a polymer basis known as an NG is sub-micron-sized [2]. NGs are highly customizable in size, shape, surface functionalization, and degradation processes and may be natural, synthetic, or a combination [33]. Based on the kind of crosslinking, reactivity to external stimuli (including pH, temperature, light, ionic concentration, etc.), and production techniques, NGs may be classified into several types (Fig. 2).

Fig. 2
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Different types of NGs

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Polymers used for NGs

Hydrophilic polymers, which typically absorb abundant water within their crosslinked frameworks, are the key components of NGs. These NGs are distinguished by their biological inertness and water sorption capabilities, which cause them to expand up to 1000 times in water, according to the 3D structure of the polymers utilized in their manufacturing (Fig. 3).

Fig. 3
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Different nature of polymers used to design to develop NGs

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Surface functionalization of NGs for delivery of drugs

Drug and biological molecule entrapment is possible using NGs. As a result, they may be used extensively in transporting genes and proteins. Both passive and active drug targeting are possible by adjusting the particle size and surface characteristics to prevent fast clearance by phagocytic cells. Controlled and prolonged drug is delivered at the desired site, increasing therapeutic effectiveness and minimizing side effects [34]. Due to their small volume, NPs can penetrate tissues, even the smallest capillaries, via paracellular or transcellular routes. NGs offer a significant drug-load capacity, a low floating density, and a high degree of stability during dispersion in aqueous mediums (Fig. 4). In comparison to other NPs, particularly in terms of drug loading, NGs show potential as suitable nanomedicine carriers [35].

Fig. 4
figure 4

Coating strategies of surface functionalization of NGs for selective targeting the cells. The figure was developed using BioRender (www.biorender.com) (accessed 14 October 2023)

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NGs: Drug incorporation techniques

Due to their incredible ability to target a wide variety of organs, NGs have been widely accepted in nanotechnology, resulting in dual nature: (a) As an HG system, which boosts their ability to load drugs, and (b) a system with nanoparticulate that enables them to reach deeper organs and tissues.

Incorporation of drugs inside the NGs may be achieved by numerous methods (Fig. 5), including-

  • Biological agents can covalently conjugate either during or after the development of NGs. Develop nanosized HGs (Table 2), mutated enzymes can copolymerize using acrylamide for inverse micro-emulsion and diluted water-based solutions. [36, 37].

  • Drug molecules are physically trapped inside NGs. Proteins have been included in cholesterol-modified pullulan NGs, and small interfering RNAs (siRNAs) have been incorporated into hyaluronic acid (HA) NGs using this approach [38, 39].

  • Drug loading through passive/diffusion, for instance, NPs and dexamethasone, can be separately introduced within the dextran lysozyme NGs via diffusion, and the NGs are agitated in excessive drug or NP solutions. Generally, the drug loading produced by these methods is small, often less than 10% by weight [40,41,42].

Fig. 5
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Various techniques used to prepare NGs

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Potential applications of NGs in the treatment of various diseases

NGs have gained significant attention from research groups worldwide. These structures have been developed to treat various pathologies, including cancer, spinal cord injury, ischemic stroke, cardiovascular diseases, wound healing, bone regeneration, psoriasis, inflammation, etc. They have also been used for delivering anaesthetic drugs. In the following sections, we will analyze the different pathologies in which NGs have been applied and tested. We will provide examples and references to highlight the importance of these formulations in nanomedicine.

NG in CNS-related diseases

Numerous drugs are used to treat CNS-related diseases and other brain disorders. Still, their low bioavailability in such organs, owing to the inadequate permeability of the blood–brain barrier (BBB), has permanently restricted their capacity to enter the brain [43, 44]. A more effective nano-system might lead to better therapy for diseases associated with the brain (Table 1). However, many current methods of brain targeting in nanotechnology involve improving drug access to the brain. Drug bioavailability has constantly been significantly enhanced by polymeric NPs, some of which can cross BBB [45]. The incorporation of NGs is an efficient nanoparticulate technology for effective brain-targeted therapy. Methotrexate (MTX), an anticancer drug, has been developed as a NG and is an extensively used chemotherapeutic drug with a vital role in malignancies and autoimmune disease treatment. MTX was added to the NG system to increase BBB permeability, and polysorbate was used to functionalize the surface [46, 47].

Table 1 Potential applications of NG and their outcomes
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NG significantly boosted the capacity and efficiency of drug loading. The in-vitro experiments confirm the NPs' suitability for brain administration. A study found that even though the drug plasma concentration decreased due to intravenous administration, the drug crossed the BBB and safely entered the brain slowly and controlled. It demonstrates that the drug was absorbed gradually and without risks into the brain. Compared with free drugs, MTX concentrations in the brain were considerably more significant in both kinds of NGs (surface-modified and untreated NGs). Results indicated that using drug-loaded NGs increased MTX concentration in the brain by 10–15 times, presenting a promising future for NGs used for brain delivery. Oligonucleotides (ODN) have also been developed as NG to target CNS against neurodegenerative diseases. Research demonstrated that NG formulations with ODN successfully crossed the BBB. When transferrin or insulin is added to the NG's surface, the effectiveness of the transport is significantly improved to the target. Compared to free ODN, the concentration of phosphorothioate ODN rose onefold inside the brain after 1 h of intravenous NG injection while decreasing twofold in the spleen and liver [48,49,50]. Another researcher developed cisplatin-loaded NGs coupled over monoclonal antibody conjugates to mark exceedingly expressed connexin 43 (Cx43), a tumour-specific membrane protein, and BSAT1, an anion transporter specific to the brain in human glioblastoma, the most aggressive and common brain disorder in the world. The cisplatin-loaded NG formulation for treating gliomas showed higher efficacy, and the survival rate of rats was increased for around 27 days compared to the control group [51].

NG in cancer

Cancer is a chronic illness that includes around 277 forms of cancer pathology [52]. Several treatments have been available, including radiation, surgeries, and targeted therapies [53, 54]. Several teams of researchers are keen on NGs since they offer an opportunity for specific delivery of drugs for cancer therapy (Fig. 6). Specific formulations and surface functionalization using particular ligands may be helpful strategies to selectively target malignant cells within the body and give non-invasive treatments [55]. NGs have the potential to cure diseases such as breast cancer. In this work, the researchers produced dextrin NG encapsulated by Plerixafor and supplied with Dox (Table 1) [56,57,58]. They coupled with the PLG-g-m polyethene glycol (PEG)/combretatatinA4 nano-formulations using azobenzene and cyclodextrin attached to polyglutamic acid (PGA)-graft-PEG methyl ether NG revealed a tumour reduction rate of 68.7%, that was increased to 91.7%. NGs based on cholesterol are a significant and actively researched method for treating cancer. This study created IL-12-loaded pullulan (CHP)-based NGs that include cholesterol [59].

Fig. 6
figure 6

Fate of NGs to act on cancer using endocytosis. The figure was developed using BioRender (www.biorender.com) (accessed 1 November 2023)

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In-vivo experiments showed that this technique may slow down fibrosarcoma development. In separate research, vascular endothelial growth factor (VEGF)-specific siRNA was administered via cholesterol-endowed cycloamylose through spermine NG, and the ability to inhibit neo-vascularization and proliferation of renal cell carcinoma [60]. Hyaluronic acid is a significant polymer incorporated to produce NGs to treat cancer. Contesting it, researchers developed a cisplatin-crosslinked hyaluronic acid (HA) NG comprising Dox [61]. Dox and cisplatin had a synergistic effect, increasing the biological activity while decreasing toxicity, resulting in favourable outcomes during in-vivo tests. The identical polymer produced a zein NG, including curcumin, crosslinking using HA, which was efficient towards a CT26 tumour model (Table 1) [62]. As a result, the scenarios provided do not represent the formulae that may be employed. The reduction-responsive polypeptide NG containing Dox demonstrate encouraging in-vivo results due to its exceptional security and cancer-inhibitory properties [63]. Researchers also developed pullulan NGs featuring similar characteristics [64]. In this approach, two independent pullulan NGs for administering Dox were formed with two distinct cross-linking agents, leading to tumour suppression (83.37%) in-vivo studies utilizing an ortho ester-modified Pluronic copolymer (acid-labile) as the crosslinking mediator. Another investigation looked into another NG composition [65]. Researchers developed a lactobionic acid-modified soy-protein NG to deliver Dox. In-vivo investigations demonstrated that this combination facilitated tumor targeting and treatment efficacy. The potential to alter the composition of NGs for selective drug release activities is an attractive feature. In this context, transferrin-modified poly-sulfamide NGs enabling Dox loading were developed [66]. In-vivo studies presented that the formulation had tumour-targeting attributes, which could improve cancer treatment. This investigation used a different approach. In this instance, they synthesize an irinotecan-loaded gelatin NG membrane with platelets embedded. The prepared NGs decrease in-vivo cancer cell growth, reducing side effects [67].

However, hepatic cancer (HCC) is thought to be the third leading cancer-related cause of death worldwide [68,69,70,71,72]. Among the most often used chemotherapeutic drugs for the treatment of liver carcinoma is doxorubicin (Dox), [73]. However, it requires an effective therapy potential because of its decreased effectiveness as a consequence of its severe toxicity. Additionally, Dox has a history of being rapidly metabolized into inactive derivatives, which further reduces its effectiveness. A composite biodegradable NG that are pH-sensitive for local injectable administration was synthesized to counteract the harmful effects of Dox, such as cardiotoxicity and the present issues with HCC [74]. The NG system target tumour tissues due to the enhanced permeability and retention (EPR) effects. It releases drugs through pH-controlled hydrolysis in endosomes and lysosomes through the endocytic route (Table 1). This results in more precise drug delivery with fewer side effects and enhanced effectiveness in cancer treatment. Chitin-poly L-lactic acid composite NGs (CNGs) successfully included Dox, with 86% entrapment efficiency. At an acidic pH, chitin-PLA and Dox-chitin-PLA CNGs resulted in more enlargement and drug release. Additionally, these NGs demonstrated no haemolysis of RBCs, demonstrating the systemic route's safety. In-vitro tests have demonstrated improved cytotoxicity employing pH-sensitive NGs, which deliver the drug with low pH, specifically where the tumour occurs without producing adverse effects via systemic drug distribution [75].

Nano formulations with appropriate surface charge and size offer a vast opportunity for cytotoxic drugs to target specific regions owing to their superior biological membrane permeability. Concerning the topical distribution of drugs through small gels, NGs among contemporary Nano formulations are gaining attention. Chitin NG of 5-fluorouracil (5-FU) is a skin cancer drug thus far produced. The study's findings led to the effective loading of 90% of the drug in the NG, which had a higher capacity for swell and drug release at an acidic pH. Although introducing 5-FU to the NG didn't enhance its penetration for various reasons, it might increase the gel's retention period for the deepest layers of skin (up to 5 times) and is advantageous since the therapy's targets, melanocytes, are found in deeper layers [76].

Moreover, hyperthermia is an abnormal elevation in body temperature or overheating [77]. Whole-body hyperthermia (WBH) and hyperthermic perfusion treatments, such as hyperthermic isolated limb perfusion (HILP) and hyperthermic peritoneal perfusion (HPP), differ from local/interstitial and regional hyperthermia [78]. Clinical investigations on people with locally advanced malignancies supported the application of regional and local hyperthermia [79]. These studies found a remarkable association between administered doses and outcomes. In phase II investigations, regional and local hyperthermia were used in addition to chemotherapy and radio-chemotherapy. The findings suggest that hyperthermia has many therapeutic benefits [80]. The initial heat-activated formulation of a liposomal carrier for drugs to be used in human clinical trials is also thermosensitive liposomal Dox (Table 1) [81]. One of the most popular antineoplastic drugs used in the treatment of human cancer is Dox [82]. The study conducted by the researchers involved the synthesis of a dual pH and temperature-sensitive PNA NG, which was used to deliver drugs. Under normal conditions, the PNA NG was hydrophilic (Table 1).

However, upon heating through its LCST (lower critical solution temperature), the NG undergoes a phase transition influenced by pH value. Because of the pH difference across cancer and normal tissues, tumour cells could preferentially absorb Dox-PNA NGs. Consequently, such NGs might deliver chemotherapeutic drugs directly to tumour cells, increasing cellular internalization during region hyperthermia therapies. Dox was covalently linked to PNA through an acid-labile bond to form NGs. The association was robust at extracellular and physiological pH, but it cleaved to release the drug when it came into contact with moderately acidic conditions in tumour cell endosomes. The approach could lessen the adverse impacts of anti-cancer drugs while boosting their ability to target tumour cells. Dox-PNA NGs may significantly enhance the combination treatment of hyperthermia and chemotherapy [83].

NG in spinal cord injury

A spinal cord injury (SCI) constitutes a devastating CNS disorder that can come from both traumatic and non-traumatic occurrences [84]. The 'primary injury' involves immediate neurological impairment to the spinal cord, and the 'secondary injury' is marked by a sequence of biochemical and inflammatory responses. In the present instance, the most essential aspect of the second stage is inflammation, which is intensively studied to develop an efficient therapeutic candidate for reducing it. The two polymer-based vehicles for drug delivery developed for the treatment of SCI are NGs and NPs. The capacity to penetrate the CNS's intrinsic barrier and selectively address its cells is essential in all conditions. In a recent study, rolipram ( an anti-inflammatory drug) was put into a PEG and PEI-NGs coated with amines (Table 1) [85]. In-vivo studies indicated that formulations might specifically target the astrocytes and restore motor functions in animal models in the initial stages of spinal cord injuries despite lowering the pro-inflammatory events triggered by the activation of astrocytes.

Similarly, a researcher developed poly lactic-co-glycolic acid (PLGA) microspheres carrying paclitaxel and minocycline hydrochloride introduced to alginate HG [86]. In-vivo examinations on rats with dual-drug regimens demonstrated that it successfully decreased inflammatory responses after seven days of treatment, scar tissue development, and neuronal regeneration after four weeks. In a study, the researcher developed a new and significant approach involving polymeric NPs [87]. They employed poly-caprolactone-based NPs loaded with minocycline to target microglia in their investigation. By regulating specific microglial cells, the acute therapy of the NGs in a mouse model with SCI reduced the pro-inflammatory responses while maintaining pro-regenerative surroundings for up to 10 week’s post-injury. SCI was also treated with minocycline. This study developed a sialic acid-PEG-PLGA co-polymer that specifically targets E-selectin and can assemble itself into micelle formulation [88]. In-vivo experiments revealed that these micelles could be assembled in SCI sites in mice, lowering the extent of the lesions and enhancing axon and myelin survival. The scientist also used polymeric NPs carrying IRF5 siRNA, which were delivered into the wounds of SCI mice [89]. Introducing these NPs altered the anti-inflammatory reaction in the wound by minimizing M1 macrophages while boosting the amount of M2 macrophages. Many conditions, other than SCI, can influence the CNS. Thus, NGs can help treat them successfully. Brain tumours, such as glioblastoma, represent an excellent illustration, as they may be highly aggressive and threatening to human life [90]. NGs have the potential to deliver immunotherapy onto glioblastoma cells in an efficient manner. They can be done by consistently developing thermo-reversible PEG-chitosan HGs designed to release T-lymphocytes [91]. These HGs have a solid capability to kill glioblastoma cells and are an essential tool for targeted immunotherapy [92].

NG in ischemic stroke

Ischemic stroke can be treated through thrombolytic treatment, which includes drugs including streptokinase, urokinase, anistreplase, and tissue plasminogen activator [93, 94]. Respondent NGs, such as pH-sensitive NGs, may be beneficial for developing urokinase delivery and are considered a practical approach in stroke management. In one instance, researchers developed pH-sensitive PEG-urokinase NGs (Table 1) [95]. When the pH drops owing to microcirculatory clots, which typically cause an oxygen deficit in this sickness, the NG releases urokinase. In-vivo studies found that urokinase was introduced one hour after cerebral artery congestion, minimizing ischemia damage by preserving the BBB, strengthening ischaemic brain tissues, suppressing apoptosis, and minimizing neurotoxicity. Another investigation [96] discovered that using the same formulation outside the conventional thrombolysis interval produced encouraging outcomes for in-vivo assessment in a second study. In this research, the loaded NGs protected the BBB and decreased stimulate-neurotoxicity among rats with chronic middle cerebral occlusion. Another study developed a hollow NG carrying urokinase (made by combining chitosan glycol and aldehyde-capped PEG) for delivering urokinase under ultrasonic diagnosis conditions [97]. In-vivo investigations revealed that this formulation might prolong urokinase circulation time. The formulation provided urokinase more rapidly, increasing clot thrombolysis, and was responsive to diagnostic ultrasonography. The present study suggested by in-vivo tests that similar urokinase-loaded hollow NGs might mitigate severe ischemic stroke by enhancing urokinase's thrombolysis consequences, maintaining the BBB's integrity, preventing adverse brain haemorrhage and death of animals after one week of administration [98].

NG in inflammation

MTX was initially developed as a folic acid antagonist in the 1940s. This drug primarily inhibits malignant cell proliferation by inhibiting the de novo production of purines and pyrimidines. Because high doses of folinic acid and folic acid may counteract MTX's antiproliferative effects, it is clear that MTX is an antifolate drug. Cells take up MTX via a folate carrier and convert it to polyglutamate [99, 100]. MTX is a potent drug used for cancer [101], anti-inflammatory, and immunosuppressant treatments [102]. It has long-lasting metabolites called MTX polyglutamate that retain the parent compound's antifolate actions while altering the potency of inhibiting specific folate-dependent enzymes [103, 104]. A further investigation examined how sodium carbonate (Na2CO3) affected the transport of MTX within a NG in vitro and the modification of prostaglandin E2 (PGE2) synthesis in skin ex vivo. A NG containing MTX was administered to resected porcine epidermal membranes. The introduction of saturated aqueous Na2CO3 boosted MTX flow while decreasing PGE2 synthesis (Table 1). The findings suggest a unique mechanism in which temperature changes caused de-swelling and ejection of MTX in situ. At the same time, the addition of Na2CO3 resulted in more solubilization and MTX release, lowering PGE2 production [105].

NG in gene therapy

Gene therapy is a legitimate therapeutic option nowadays. However, the initial clinical trials were discontinued due to serious adverse effects [106]. Two out of ten patients who underwent retroviral gene therapy for X-linked severe combination immunodeficiency (X-SCID) developed T-cell leukaemia [107]. Indeed, among the most promising areas of gene therapy is RNA interference (RNAi), which employs siRNAs [108]. Antisense RNA (asRNA) was initially utilized for gene silencing in rats, and this work found that long dsRNA triggered selective mRNA degradation in C. elegans. The sense and antisense strands within dsRNA produced up to tenfold quieter than either strand alone, resulting in Post Transcriptional Gene Silencing (PTGS). After RNAi was discovered in lower eukaryotes, biomedical researchers found it also occurs in mammalian cells [109,110,111]. A new method for delivering siRNA into cells has been developed using a platform called cationic dendritic polyglycerol (dPG-PEI) NG (Table 1). This platform has demonstrated a similar transfection performance to the conventional 25 kDa branched polyethyleneimine (PEI), significantly reducing cytotoxicity. The NG synthesis method employs a thiol-Michael nano-precipitation approach, allowing sensitive contents to be added directly during the NG synthesis. pH-sensitive benzacetal linkages in the NG network help to release the content. The cationic NG platform represents a ready-for-use transfection solution that may be administered directly to cells without requiring complex polyplex production techniques. The new platform ensures that polyplexes and their exact sizes are specified irrespective of the preparation technique [112].

NG in cardiovascular diseases

These are the significant causes of death globally [113]. It covers a variety of diseases, including cerebrovascular, venous thromboembolism, peripheral artery, congenital and coronary heart disease [114]. Various factors, like genetics, hypertension, diabetes, and obesity, can cause cardiovascular diseases. Several researchers are exploring using NGs to deliver drugs to treat these diseases (Fig. 7). Multiple approaches are available to treat hypertension. Still, a novel therapy option has been found that can also treat pneumococcal pneumonia. The technique employs drug nanocarriers to provide an intranasal vaccine (Table 1) [115]. The novel therapy involves cationic-charged cholesteryl-pullulan NG bearing Pneumococcal surface-protein A (PspA) and Angiotensin 1 Receptor (AT1R) from the pneumococcal surface. AT1R antagonists efficiently decrease blood pressure, excluding side effects in rat models. PspA can trigger immunity against Streptococcus pneumoniae. This novel therapy has the potential to alter the treatment of hypertension and pneumococcal pneumonia. In-vivo studies have shown that immunization effectively avoids lethal pneumococcal infections by lowering blood pressure. Another study presents a distinct approach to treating hypertension using NG compositions [116]. The researchers developed NG of amphiphilic Karaya gum with a 3.24 propyl group substitution to distribute Bosentan monohydrate inside the colon selectively. In-vivo studies demonstrated that the NG could effectively lower blood pressure for up to 10 h following delivery, with the most significant decrease occurring after 8 h, reducing by approximately 31%. Besides hypertension, other potential cardiovascular disease treatments use NG-based drug delivery systems. This study developed an N-isopropylacrylamide-methyl methacrylate NGs to administer N, L-rhamnopyranosyl vincosamide and determine cardioprotective attributes. The study revealed that these NGs have intriguing cardioprotective capabilities [117]. In-vivo studies demonstrated that these structures could significantly reduce heart damage in the Dox-induced toxicity model. In further studies, researchers developed temperature-sensitive poly (N-isopropyl amine-co-acrylic acid) NGs containing cardiac stem cells of humans to treat myocardial infarction. These NGs were in-vivo against mouse and pig models, proving their capability to decrease scar size and maintain heart function without causing systemic inflammation [118].

Fig. 7
figure 7

Schematic representation of treatment of cardiovascular disease (myocardial infection) using NGs. The figure was developed using BioRender (www.biorender.com) (accessed 7 November 2023)

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NG in wound healing

The wound healing process consists of four phases: inflammation, proliferation, production of the extracellular matrix components, and remodelling [119, 120]. This biological process involves various elements, including keratinocytes, platelets, immunological cells, fibroblasts, and microvascular cells [121]. Historically, various compounds, especially those derived from plants with medicinal properties, have been utilized to accelerate wound healing [122]. Nanocarrier-based techniques, like NGs, have been extensively researched to enhance treatment effectiveness and targeted delivery of active substances. During the process of wound healing, there is a possibility of infection. Researchers have developed chitosan-based NGs packed with an antibacterial drug called silver sulfadiazine to tackle this issue. These NGs were then compared to commercial formulations containing the same chemical (Table 1) [123]. The results of in-vivo experiments have shown that the NGs are an effective treatment for burn wounds. The concentration of silver sulfadiazine necessary to accomplish this effect is lesser than that of commercial formulations [124]. Their research created a lysine-based NG with the antiseptic/disinfectant chemical chlorhexidine diacetate. The loaded NGs were combined with HGs containing methacrylate methoxy PEG and aminoethyl methacrylate HA. In-vivo studies have shown that HGs containing loaded NGs possess strong antibacterial capabilities, as no bacterial biofilm was detected.

Additionally, these HGs were observed to have a quick hemostasis outcome, hastening the healing process. Researchers have also explored alternative methods of controlling inflammation during wound healing. Scientists synthesized gellan-cholesterol NGs carrying baicalin, a flavone often used to treat inflammatory conditions [125]. In-vivo studies demonstrated that these NGs suppressed several inflammatory markers, such as TNF- and myeloperoxidase, more efficiently than marketed formulations and baicalin in phosphate buffer solution. Natural compounds, like curcumin, have demonstrated remarkable wound-healing properties. In another study, researchers created NGs containing fish-scale collagen-HPMC to treat related diseases [126]. In-vivo, studies have shown that combining collagen with curcumin improves wound tightening and reduces irritation symptoms compared to alternative curcumin preparations. IL-2 is a different significant molecule in the healing process because of its positive effect on T-lymphocyte formation. The researchers designed a chitosan-based NG containing IL-2 [127], which provided exciting in-vivo results revealing a reduction in malondialdehyde, a lipid peroxidation biological indicator, and a rise in glutathione concentration. This renowned antioxidant had positive results towards wound recovery applications. In a different study, researchers developed heparin-modified pluronic NGs containing the VEGF195 and BFGF genes, stimulating wound site neovascularization [128]. In-vivo studies revealed that this composition effectively increased endothelial differentiation of cells and neovascularization.

NG in bone regeneration

Bone diseases constitute one of the most prevalent causes of disability globally. Fractures, osteoporosis, and tumours are among the pathologies that cause bone diseases (Table 1) [129]. When bones are healthy, they may reestablish themselves without forming tissue with scars [130]. Fortunately, specialized treatments are frequently needed, like the application of bone alternatives with osteoconductive and osteoinductive properties, as well as the utilization of cells such as mesenchymal stem cells (human), growth factors including bone morphogenic proteins (BMP), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelets-derived growth factor (PDGF) [129]. In this instance, scientists have developed pullulan NGs containing cholesteryl and acryloyl [131]. Recombinant human FGF18, which is used to enhance the activity of low BMP2 doses, and recombinant human BMP2 were produced using these frameworks to generate fast degradable HGs. In in-vivo studies, these formulations induced bone regeneration more efficiently than free BMP2 or a mixture of independent BMP2 and FGF18. The study showed an alternative method for using BMP2 to induce bone healing [132]. To deliver BMP2, the investigators combined polycaprolactone (PCL) with redox-sensitive c-6A PEG-PCL NG (Table 1). This combination yields nanofibers with a core–shell configuration. In-vivo investigations revealed that the NGs controlled distribution of BMP2 might promote bone defect repair.

Similarly, in a different research p-(N-isopropylacrylamide-co-butyl methylacrylate), NGs were designed to develop moieties that function as carriers for delivering mesoporous bioactive surface. The findings (in-vivo) indicate that the bioactive glass-loaded NG-based framework may aid in the repair of femur deformity in osteoporotic animals. The W9-peptide, a TNF-α and receptor activator of kappa beta antagonist, is a potent molecule that has the potential to accelerate bone regeneration. Scientists developed a CHP NG that delivers the W9 peptide [133]. Their research concluded that this framework might prevent the loss of bone in bone resorption models in-vivo. PGE2, a nonpeptide anabolic molecule, may also help with bone rebuilding. The substance's high dosage and short half-life lead to adverse effects. Researchers produced a CHP NG for PGE2 to address these issues [134]. In in-vivo assessments, PGE2 encouraged new bone development when paired with an HG sphere that cross-linked NGs.

NG in psoriasis

Psoriasis is a persistent, inflammatory skin disorder that affects 1–3% of the global population [135]. Because T cells in the epidermis and dermis are activated, it is an immunologically mediated illness [136]. Traditionally, various dosage forms of MTX, retinoids, and cyclosporin are used to treat psoriasis. Various NG preparations have been developed to distribute this type of medication effectively. In this work, scientists proposed a vital method to address this issue [137]. They formulate chitin-based NGs containing clobetasol (CLCNG) for skin application (Table 1). In their study, they compared the effectiveness of prepared NGs to commercial costate cream, and results suggested that CLC NG attained equal anti-psoriatic properties with reduced skin irritation, which made it a suitable choice for skin application.

Moreover, the same team developed an MTX-loaded chitin NG for topical use (Table 1) [138]. They achieved an overall Psoriatic Area and Severity Index (PASI) reduction of 73.11–89.22% (depending on drug dose) using these NG formulations, which was greater than the ideal reduced percentage (73–75%) for taking into account them clinically valuable, demonstrating anti-psoriatic property. They also compared their simplicity for use with a commercial MTX gel, which showed a lower PASI drop and no adverse induction. In a second experiment, they discovered that their MC NG outperformed traditional MTX oral tablets because of their lower toxicity induction [139]. Babchi oil, a naturally existing essential oil with fewer adverse effects than other produced medications, is another helpful constituent in psoriasis treatment. Cyclodextrin-based NGs carrying Babchi oil for application on the skin were developed to test their efficacy for psoriasis therapy by comparing their effectiveness to the native Babchi oil gel [140]. Their in-vivo investigations revealed that these NG were effective against psoriasis without producing visible skin irritation, inflammation, or erythema. Earlier studies indicated that MiRNA-210 plays a crucial role in this type of disease. A high-density lipoprotein NG carrying miR-210 antisense was developed, and its efficiency in reducing inflammation comparable to psoriasis in mice was demonstrated in the study, indicating its potential use in topical treatments [141].

NG in diabetes

MIT and Boston Children's Hospital researchers are developing a self-operating insulin delivery system utilizing a unique nanotech technique comprising just one NG injection stabilizing blood glucose levels for up to 10 days. Due to its glucose sensitivity, the NG can monitor glucose levels and release insulin as necessary. The MIT method uses NG of a combination of oppositely charged dextran NPs, which are attracted to one another electrostatically and help the gel maintain its mechanical consistency. The inner core of the NPs comprises glucose oxidase, modified dextran, and insulin. When exposed to high blood glucose levels, the enzyme transforms glucose into gluconic acid. The dextran spheres are broken down by the gluconic acid that has thus been generated, which also releases insulin, bringing the blood glucose level back to normal. Due to biocompatibility, Dextran and gluconic acid eventually disintegrate in the body [142, 143]. In recent years, a poly (4-vinylphenylboronic acid-co-2-(dimethylamino) ethyl acrylate) [p(VPBADMAEA)] silver NP NG with insulin loading has been developed (Table 1). In the research, the polymer-bound Ag NPs were given the glucose-sensitive p(VPBADMAEA) shell, which caused the Ag NPs to react to glucose. The glucose-responsive polymer, p(VPBADMAEA), detects any variation in the concentration of glucose in the blood throughout a therapeutically meaningful range (0–30 mM) and converts this variation into an optical signal that is recognized by the optically responsive silver core (10 ± 3 nm) [144].

Challenges and future perspective

NG drug delivery systems represent a promising frontier in medical science, addressing challenges in conventional drug administration. NG offers a unique platform for controlled drug release, enhancing therapeutic efficacy while minimizing side effects. However, their widespread application faces several challenges. One primary obstacle is the intricate design required to optimize drug encapsulation and release kinetics. Achieving a balance between stability and responsiveness is critical to ensuring the NGs effectively deliver drugs to target sites.

Moreover, the potential toxicity of nanomaterials and their long-term effects on the body demand a thorough investigation and regulatory scrutiny. Another challenge involves the scalability of NG production. Developing cost-effective manufacturing processes that maintain consistent quality poses a hurdle in translating these innovations from the lab to large-scale clinical applications. Despite these challenges, the future perspective of NG drug delivery is highly promising. The versatility of NGs allows for tailored solutions to treat various diseases. In oncology, for instance, NGs can enhance the specificity of chemotherapy, redutreatcing damage to healthy tissues. Neurological diseases may benefit from targeted drug delivery across the BBB, improving treatment outcomes. Moreover, the advent of smart NGs, responsive to specific physiological cues, further amplifies their therapeutic potential [169, 170].

As research progresses, addressing challenges and refining NG technologies will propel them into mainstream medical practice, revolutionizing drug delivery and significantly improving patient outcomes across a spectrum of diseases. The collaboration between researchers, clinicians, and regulatory bodies will be instrumental in realizing the full potential of NG drug delivery systems in the future of medicine [83, 171,172,173,174,175].

NG: Status of patents for treatment of various diseases and their marketed products

The status of NG contain therapeutic agents used for treatment of various diseases and marketed products are showed in Table 2 and 3 respectively.

Table 2 Patents on NG used for treatment of various diseases
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Table 3 Marketed products of NG used for treatment of various diseases and their brand name
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Conclusion

NGs, versatile nanoscale structures, exhibit immense potential in revolutionizing medical treatments across various diseases. Their unique properties, such as high surface area and tunable drug release kinetics, make them promising candidates for targeted drug delivery. In oncology, NGs have shown remarkable efficacy by delivering chemotherapeutic agents directly to cancer cells, minimizing collateral damage to healthy tissues. The application of NGs extends beyond oncology; they have successfully treated inflammatory diseases, tumours, liver disease, SCI, infections, cardiovascular diseases, hyperthermia, diabetes, and neurological diseases, and also in the biomedical field. Their adaptability allows customization to suit specific therapeutic needs, heralding a new era in precision medicine. However, the journey from the laboratory to clinical implementation is fraught with challenges. One significant hurdle is ensuring the biocompatibility and safety of NGs. Ethical concerns surrounding the long-term impact of NGs on the human body necessitate thorough investigation.

Moreover, scalability and cost-effectiveness are addressed to make these innovations accessible on a global scale. The ongoing clinical trials involving NGs are crucial milestones to determining their real-world viability. Researchers are diligently evaluating their performance, side effects, and therapeutic impact. Looking ahead, the future of NGs appears bright. Continued research and advancements in nanotechnology promise to overcome current challenges, fostering widespread adoption of NG-based therapies. NGs may be pivotal in this paradigm shift, offering precise and efficient strategies for many medical conditions.

In conclusion, NGs represent a groundbreaking innovation with far-reaching implications for medical science. While challenges persist, ongoing clinical trials and a commitment to rigorous research pave the way for a future where NGs become indispensable tools in the fight against various diseases, offering hope for more effective, targeted, and controlled treatments.