One of the most recognized complications of DM is DNP. In various studies across India, PN prevalence ranges from about 10.5% to 32.2% in diabetic patients (18). Compared to the West, it has a higher prevalence of DM in India (4). Nowadays, practically in every country, diabetes impacts the population and increases medical load. Diabetes has become an epidemic globally; nearly 463 million adults in the age group of 20–79 years had diabetes in 2019, and this number is projected to grow to 700 million by 2045 (19). In Indian epidemiological studies from different areas, the average prevalence of PN in various community studies ranged from 5 to 2,400 per 10,000 population (20). Pain is one of the most pronounced symptoms of diabetic polyneuropathy. The incidence of diabetic peripheral neuropathy (DPN) was 46% in the African population in a survey conducted in 2020. Apart from this, the highest prevalence was reported in West Africa, accounting for about 49.4% (21). In autonomic neuropathy, the extent to which symptoms occur is relatively low (0%–10%), except impotence, whose chances of occurrence are about 5%–50% (22). As per reports from Europe and the USA in the year 2007, it has been revealed that the prevalence of DPN ranges from 6% to 51% with successive years of follow-up (13–14 years) (23). The pervasiveness of DPN in adults increased to 30% from 6% in type 1 diabetic patients as per the study conducted by Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) (24). A survey from the Consensus Development Conference on Diabetic Foot Wound Care suggested that around 26% of youth with type 2 diabetes developed DPN, thereby concluding that type 2 diabetics are more prone to develop neuropathic pain (25). Foot ulceration is one of the common manifestations of diabetic neuropathy. In some patients (14%–24%), foot ulceration is so severe that, sooner or later, it requires amputation (26). Patients with a previous history of foot ulcers, foot malformation, poor sugar control, smoking, etc., are at higher risk of amputation (27). Older adults are more prone to diabetic neuropathy who have had chronic diabetes for a long time (28). Some studies demonstrated that diabetic neuropathy is less observed in the Asian population, although there was no evidence or finding supporting this particular statement (29). More recently, DPN’s prevalence has been reevaluated in young people with shorter durations of diabetes.

DRG is one of the most condemning structure in sensory signaling and modulation, along with pain transmission (30). A very thin boundary of cerebrospinal fluid (CSF) surrounds the sural sheath in which DRG is located (31). DRG is a mere extension of the dorsal root that usually accommodates cell bodies of primary sensory neurons (PSNs). The diameters of cell bodies can be classified as large-light neurons (which are generally known as A-neurons, and these usually transmit non-noxious information) or small-dark neurons (traditionally known as C-neurons, which transmit painful signals) (32). The axon soon gets bifurcated into a T-like fashion into a peripheral branch, which is connected with somatic and visceral receptors, and finally enters into a central component that ends up into a cord (33). The DRG’s root sheath covers the dorsal root cord and traverses the subarachnoid space toward it. The proximal part usually consists of numerous tiny rootlets entering the dorsolateral cord in a defined manner (33). The DRG central projections typically end up in the corresponding segment. DRG is in close association with the sympathetic chain via rami communicantes nerves. Sometimes, these nerves can act as channels for discogenic afferents that can deliver spinal pain signals to the DRG (34) ( Figure 1 ).

The pathophysiology of DNP is quite complex, and there is no complete evidence to understand it entirely. Arteries endowing peripheral nerves undergo numerous changes and have been considered one reason behind aches and pains related to diabetic neuropathy. Recently, variations in sodium and calcium channel expression and central pain mechanisms have been linked to pain (39). Moreover, DNP is manifested by various risk factors, including old age, smoking, alcohol intake, and long-term diabetes (40). Due to a reduction in heat- and cold-specific C fibers and Aδ fibers, respectively, neuropathy leads to cold and heat allodynia (41). Mitochondria malfunctioning causes many problems in the body such as induction of neuropathic pain and changes in the peripheral nervous system (42). Various mitochondrial mechanisms, including calcium regulation (43), production of reactive oxygen species (ROS) (44), and apoptotic signaling pathways (45), are significantly involved in the development of neuropathic pain. Therefore, it is not only one single pathway that causes pain, but so many interconnected pathways operate together to start the cascade leading to neuropathic pain.

Changes in sodium channel expression appear to be triggered by hyperglycemia. In pain models of neuropathy, upregulated sodium channels (voltage-gated) were commonly seen in the DRG (46). Impairment of Na⁽⁺⁾-K⁽⁺⁾ pump occurs basically due to hyperglycemia, and it affects Na⁽⁺⁾ currents to a great extent (47). Along with their transmission, these channels impact action potential processing and can be regarded as tetrodotoxin sensitive (TTX-S) (48). Tetrodotoxin-sensitive Nav1.3 channels are usually upregulated in diabetic animal models (49) and Nav1.7 in the DRG (50) (51, 52). Na⁺ channels are repeatedly opened due to sensory neurons of DRGs, and their opening duration has also been seen to be prolonged to elevate the levels of intracellular sodium ions. Due to polarization of the neuron, there is increased opening of calcium channels that further leads to hyperpolarization (47). Rats in which nerves of the spinal area are injured show the oversensitivity of nociceptive responses to harmless mechanical stimulation due to overexpression of α2δ-1 subunit of the calcium channel (53). Due to this overexpression, more calcium enters the cell, leading to various signaling cascades (53). Also, the release of glutamate in the presynaptic zone leads to stimulation of N-methyl-D-aspartate (NMDA) receptors. This activation of the NMDA receptor will enhance the influx of calcium into the cell, thus rising calcium levels intracellularly (54). In response to the hyperpolarization of cells, mitochondria start releasing more calcium in the cytoplasm from its intercellular stores. As calcium concentration elevates inside the cell, it leads to activation of various signaling cascades mainly involving phosphorylation of PKC (55), causing an upregulation of TRPV (56), which directly causes variations in the sensory neurons, which result in a hyperresponsive state. There is the generation of nitrogen and oxygen-free radicals due to the upregulation of TRPV, leading to neuronal cytotoxicity (57).

TRPV1 coresides with transient receptor potential ankyrin 1 (TRPA1) in particular neurons of DRG, and it is proven to have a role in the generation of the pain signals and in inflammation that may occur due to various irritants such as chemical agents, ROS, or nitrogen radicals (58). Increased permeability of mitochondrial permeability transition pores (mPTPs) due to hyperpolarization inside the neuronal body may cause the release of cytochrome C that further begins apoptotic cascades. During the apoptotic pathways, caspases get activated, which can cause the destruction of neuronal bodies and can cause cellular toxicity (59). Consequently, the number of cold-specific Aδ fibers and heat-specific C fibers starts reducing from the epidermis, known as loss of intraepidermal nerve fibers, and loss of nociceptors has also been observed that will result in the hyperresponsive state of the remaining nociceptors (60). Various inflammatory mediators involving tumor necrosis factor (TNF)-α, interleukin-1 (IL-1), and IL-6 are also seen to be involved in this signaling cascade. Cytokines, after binding to their receptors, lead to activation of PKC and MAPK that further corresponds to the development of neuropathic pain (61). These inflammatory cytokines usually enhance the expression of various ion channels involving sodium channels that causes neuronal excitotoxicity and significantly contributes to neuropathic pain pathogenesis (62). The pathogenesis of DNP interconnecting different pathways is represented in Figure 2 .

The main drawback offered by drugs used in the treatment of diabetic neuropathy was their toxicity. Hence, incorporating them into nanocarriers greatly enhanced their efficacy and reduced their toxicity. In addition, many side effects were accounted for with traditional treatment such as lack of specificity and adverse effects such as light-headedness, languidness, and multiple daily doses (68). The latest treatments do not provide adequate pain relief for about half of the patients and offer many undesired side effects such as somnolence and dizziness and the requirement of a complex dose regimen to reduce patient compliance. Standard agents for topical administration are there for the treatment of DNP, such as capsaicin cream, which is without any side effects. Still, they have low efficiency, and complex multiple administration is required, which can cause discomfort, and also the chances of contamination of sensitive body areas are also there, both of which can lead to poor patient compliance (69) ( Table 1 ). The basis of this study is to incorporate novel nanotechnological approaches in mitigating DNP by targeting the DRG. Previously, opioid analgesics were widely used to treat DPN (13). Unfortunately, severe side effects were seen in patients exposed to this drug therapy. It mainly arises due to its action on the receptors present in the CNS, leading to respiratory depression, sedation, dizziness, etc. Here, nanotechnology outperforms in every aspect by delivering sensitive and targeted treatment. Another point to be taken into account is the uncontrolled drug delivery and frequent administration of drugs offered by traditional delivery systems. This probably leads to changes in plasma drug levels, thus increasing the demand for novel approaches (70).

With recent progress in identifying pain-generating processes and adopting evidence-based treatments, patients suffering from DPN are still difficult to cure. The latest treatments do not provide adequate pain relief for about half of the patients and offer many undesirable side effects such as somnolence and dizziness and the requirement of a complex dose regimen that reduces patient compliance. In addition, due to the lack of specificity of drugs, there is inadequate relief of pain. Ultimately, more understanding of the basic pathophysiological processes that lead to this complication should make it possible to devise optimal therapies for individual patients suffering from neuropathic pain (69).

Nowadays, diabetes is one of the most widespread and long-term diseases affecting most people globally (71). As per recent estimates, in the course of a year (2020–2021), the global diabetic neuropathy market is appraised to expand at a compound annual growth rate (CAGR) of 5.9%. In 2011, around 366 million people had diabetes, and the count is estimated to significantly rise to 522 million by 2030, as per approximation given by the International Diabetes Federation (72). Therefore, we can say that shortly the DNP market has stupendous opportunities to flourish. However, most of the formulations are sold by their generic names due to which there is an excellent hindrance in introducing all new and innovative therapeutic agents.

On the other hand, there has been a significant emergence and rise in the diabetic drug market after approval by the Food and Drug Administration (FDA) on using novel drugs for treating DNP. Various medications were approved, out of which two were widely used, namely, Nucynta ER and Lyrica, in 2015. The rise in the market is commonly observed in five areas, namely, Asia Pacific, South America, North America, Europe, and Africa. Among all these, North America holds the biggest market for diabetic neuropathy, where around 7.9% of adults have a chance of developing diabetes. Moreover, type 2 diabetes is directly related to obesity, hence in the US, with rising cases of obesity, there are great chances of developing DNP, thus depicting enormous market scope (73).

Hence, with comprehensive understanding about the disease, we move forward to understanding about the novel nanotechnological as well as other approaches for targeting the DRG for the treatment of neuropathic pain.

Nanoparticles represent a massive variety of particles, mainly particulate materials less than 100 nm (74). Nanoparticles exhibit remarkable and distinctive mechanized, chemical, and optical characteristics, making them a consummate agent for treating DNP. A study indicated that the CeO₂ (cerium oxide) nanoparticles play a significant role in combating oxidative impairment and showed protective actions on diabetic neuropathy. Compared to the control group, diabetic rats showed a higher nociceptive threshold. After treatment with CeO₂ nanoparticles, the pain threshold was reinstituted to the standard level. This study proved to be significantly successful in revealing the CeO₂ nanoparticle as an excellent agent that suppresses nerve damage due to diabetes (75). Another study demonstrated the potential benefits of curcumin incorporated into nanoparticles in mitigating DNP arbitrated by P2Y12 receptor on SGCs in DRG. In diabetic rats, thermal hyperalgesia occurs due to modulation of IL-1 and Cx43. When curcumin nanoparticles were administered in the DRG of rats, the expression of IL-1 and Cx43 reduced significantly. Therefore, it can be said that curcumin nanoparticles are an effective therapeutic agent for treating DNP (76). One study examined the effects of emodin nanoparticles on DNP initiated by P2X3 receptors in DRG. After administration of emodin in DRG of rats, there is a significant reduction in the modulation of P2X3 receptors, thus alleviating DNP and suppressing all the channeling related to P2X3 receptors in DRG neurons (77).

One of the highly recommended drug delivery systems, nanoemulsion, consists of oil, surfactant, and water in relevant ratios. Nanoemulsion bears an average atom size of 1–100 nm (68). These are widely used (88). Various experiments have been conducted to determine the potential of nanoemulsion incorporating Bauhinia variegata to treat diabetic peripheral neuropathic pain via the acupuncture technique. Due to its polyphenol and flavonoid content, Bauhinia exhibits free radical-scavenging properties. Experimental rats were administered streptozocin, employing intraperitoneal injection to induce diabetes. Administration of Bauhinia variegata nanoemulsion normalized blood glucose levels compared to the control group. Long-term treatment with nanoemulsion effectively reduced hind paw abolition latency and alleviated allodynia. Therefore, through the above experiment, one can presume that Bauhinia nanoemulsion could effectively relieve peripheral neuropathic pain (89). Furthermore, α-eloestearic acid, one of the main constituents of the bitter gourd when administered orally in the form of nanoemulsion to diabetic rats, showed promising effects by reducing neuropathic pain (90).

Liposomes are the most widely used nano delivery system, as they can significantly increase drug efficacy while minimizing their side effects. Liposomes consist of an aqueous core encircled by phospholipid bilayers (91). Ropivacaine is a widely used anesthetic for mitigating neuropathic pain (92). To alleviate long-term neuropathic pain, it was seen that liposomal preparation of ropivacaine (Rop-DPRL) could lead to the cytotoxicity of cancerous cells via nutrient destitution. Another study demonstrated the effects of zoledronic acid (ZOL) in mitigating neuropathic pain. The most pronounced drawback of ZOL is its pharmacokinetic outline. Hence, an animal model developed and assessed ZOL incorporating PEGylated liposomes (LipoZOL) for its action in attenuating neuropathic pain. There is partial or complete disorganization of the blood–brain barrier (BBB) in chronic neuropathic pain, which permits the safe entry of nanocarriers such as LipoZOL. Changes in BBB due to sciatic nerve destruction encourage the invasion of LipoZOL in the dorsal horn of the spinal cord, thereby administering adequate concentrations of ZOL in the CNS. This further regulates the phenotypical shift of glial cells, thus alleviating neuropathic pain (93).

Exosomes are small vesicles that are seen in body fluids. Exosomes are acknowledged for their excellent capacity for loading nucleic acids and are less toxic than other novel carriers such as carbon nanotubes and fullerenes (94). They are primarily apprehended for their enhanced action, as they serve as carriers for numerous molecules, including proteins, nucleic acids, and lipids. As we know, RNAse leads to the destruction of miRNA, so it was loaded into extracellular vesicles to prevent its degradation. These exosome-loaded miRNAs impact physiological responses in beneficiary cells by controlling gene expression (95). Superoxide dismutase (SOD)-loaded polymersomes are highly beneficial in treating neuropathic pain, as they possess antioxidant action. These SOD-loaded polymersomes have several advantages such as appropriate interaction of the enzyme with ROS due to porous membrane and enzymes maintained their original shape. Treatment with SOD-loaded polymersomes is much effective for treating neuropathic pain as compared to SOD alone after painful DRG compression (96).

Neuromodulation is a rapidly emerging area of pain medicine that influences hundreds of thousands of patients dealing with several disorders globally (101). It involves the utilization of noninvasive and surgical electrical therapies. In the case of PDN, neuromodulation seems to be a very effective treatment option for those patients who are generally insensitive to conventional pharmacotherapy (102). Therefore, the exemplary treatment method, namely, tonic spinal cord stimulation (t-SCS), has been incorporated. It mainly involves the entry of regular electrical pulses into the dorsal column via epidural electrodes. The electrical pulses are delivered at a frequency of around 50 Hz (103). DRG stimulation or neuromodulation can effectively cause a reduction in chronic pain associated with PDN (104). DRG and DNP-DRG may be particularly susceptible to this disease for several reasons such as the following:

a) DRG consists of sensory neurons, which are not protected from the BBB, and the ambient oxygen tensions in DRG are pretty low. These physiological conditions may suggest that these may be vulnerable to microangiopathy, which is a complication related to diabetes (105).

b) Also, the involvement of sensory neurons in early diabetic polyneuropathy may put forward the fact that diabetes specifically targets DRG. Certain features associated with DRG might imply that it would be exposed to changes known to occur in diabetes such as excessive polyol flux, microangiopathy, and protein glycosylation (106).

c) Several studies, including streptozocin-induced DPN, also highlighted the fact that DRG is closely related to painful DPN acquiring several metabolic and immunological processes (107).

d) Certain receptors such as TRPV1 present in DRG are closely associated with DNP (108).

Several techniques are available to mitigate DNP, but neither glucose control nor the symptomatic treatment is very successful in doing so. Therefore, to overcome this issue, a concept has been taken into account that hypothesizes the study of patient characteristics. The concept could possibly be helpful to stratify individuals, thus providing them specific and targeted therapy to get better pain relief. This whole concept of studying patient characteristics [clinical features, quantification sensory testing (QST), genetics, and cerebral imaging] and then developing targeted therapy is termed “precision medicine” (109).