In this study, the process of manufacturing nanohydrogels containing papain and how to release it was investigated. Chitosan nanohydrogels and chitosan-polyethylene glycol hybrid nanohydrogels were used to entrapment of papain as a protein model. In order to evaluate and confirm different properties of nanohydrogels such as size, shape, the rate of swelling and flexibility, different methods was used. The maximum amount of papain entrapment was observed in 0.75% concentration of chitosan and 1% concentration of sodium Tripolyphosphate (TPP) as linker. The results of scanning electron microscope (SEM) and X-ray diffraction (XRD) patterns showed that nanohydrogels containing papain on a nano scale are very porous and swollen. Differential scanning calorimetry (DSC) thermograms analysis showed that nanohydrogels have relatively good water absorption capacity. Also, by adding polyethylene glycol to chitosan, the melting temperature of hybrid nanohydrogels decreased and this can be a reason for the formation of flexible structures in these nanohydrogels. In chitosan nanohydrogels, the highest release rate of papain was observed at pH lower than 7 and high temperatures, but by adding polyethylene glycol to the chitosan, in addition to increasing papain release, a proper and continuous release of papain was observed at temperature and pH close to physiological conditions, especially at low ratios of polyethylene glycol. According to the present results, hybrid nanohydrogels can have a good potential in protein delivery systems in terms of structure and release.

Background/Objectives: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for 15-20% of all breast cancer cases. TNBC is very difficult to treat with conventional treatment modalities such as chemotherapy, radiotherapy, and surgery; Methods: In this study, we developed a dual-loaded targeted nanotherapeutics against TNBC to solve the challenging problems associated with TNBC treatment: lack of efficacy, toxicity, and poor site-specific drug delivery; PEGylated methacrylate-polylactide copolymer containing cisplatin was synthesized and characterized; Results: The copolymer was used to fabricate nanoparticles (NPs) in the presence of paclitaxel with 1.33% drug loading. The nanoparticles were homogenous, with an average particle size of 198 nm and a negative zeta potential (-41.3 mV). Cetuximab (CTX), a monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), was attached to the NP's surface to enhance the targetability to TNBC. In vitro studies including cell uptake and cytotoxicity in MDA-MB-231 cells confirmed that CTX-targeted NPs have the potential for treating TNBC. The IC50 of CTX-NPs after 96 h of incubation was 0.1 μM, which was significantly lower than those of p-NPs (0.49 μM) and free drugs (PTX + cPt: 0.57 μM); Conclusions: In summary, this research shows that CTX-targeted polymeric NPs containing cisplatin and paclitaxel are effective in treating TNBC in vivo investigations are ongoing.

The central nervous system (CNS) diseases are major contributors to death and disability worldwide. However, the blood-brain barrier (BBB) often prevents drugs intended for CNS diseases from effectively crossing into the brain parenchyma to deliver their therapeutic effects. The blood-brain barrier is a semi-permeable barrier with high selectivity. The BBB primarily manages the transport of substances between the blood and the CNS. To enhance drug delivery for CNS disease treatment, various brain-based drug delivery strategies overcoming the BBB have been developed. Among them, nanoparticles (NPs) have been emphasized due to their multiple excellent properties. This review starts with an overview of the BBB's anatomical structure and physiological roles, and then explores the mechanisms, both endogenous and exogenous, that facilitate the NP passage across the BBB. The text also delves into how nanoparticles' shape, charge, size, and surface ligands affect their ability to cross the BBB and offers an overview of different nanoparticle classifications. This review concludes with an examination of the current challenges in utilizing nanomaterials for brain drug delivery and discusses corresponding directions for solutions. This review aims to propose innovative diagnostic and therapeutic approaches for CNS diseases and enhance drug design for more effective delivery across the BBB.

Timolol maleate (TM), a hydrophilic small molecule, is widely used in the clinical management of glaucoma. However, the complex physiological barriers of the eyes result in suboptimal bioavailability for traditional ophthalmic formulations. To address these challenges, we have developed an innovative pharmaceutical formulation. The nanoparticles (NPs) were formulated by a multi-step optimization process involving a Plackett-Burman design (PBD), steepest ascent design (SAD), and Box-Behnken design (BBD) to obtain TM-HA/CS@ED NPs. It was then encapsulated in an in situ gel (ISG) system consisting of deacetylated gellan gum (DGG) and xanthan gum (XG) to yield the TM-HA/CS@ED NPs ISG. The formulation demonstrated favorable safety in a series of ocular irritation assays and was characterized as a pseudoplastic fluid by rheological analyses, enhancing spreadability on the ocular surface and prolonging the retention time. Moreover, the NPs exposed after ISG dissolution exhibited strong mucosal adhesion and hydrophobicity, facilitating the hydrophilic TM to penetrate the corneal barrier. In vitro and in vivo retention evaluations and tear elimination pharmacokinetic study confirmed that TM-HA/CS@ED NPs ISG showed superior precorneal retention ability, and favorable sustained drug concentrations, resulting in sustained and stable transcorneal permeation into the eyes and significant intraocular pressure (IOP) lowering efficacy with a duration of 12 h. These results provide valuable insights into the design of ophthalmic drug delivery systems for water-soluble drugs and therapeutic interventions for glaucoma.

Rheumatoid arthritis is an autoimmune disorder affecting multiple joints and requires lifelong treatment. Present study was designed to formulate Esculin-loaded chitosan nanoparticles (ENPs) and evaluation of its anti-inflammatory and anti-arthritic action. The acute toxicity study of ENPs was also performed. ENPs were synthesized using the ion gelation method and their characterization was done. The formulated ENPs had a particle size of 205.1 nm, a polydispersity index of 0.574, zeta potential of 3.6 ± 0.1 mV, and entrapment efficiency of 68%, SEM analysis showed round spherical and irregularity from the outer surface, XRD revealed amorphous nature. Drug release from the carrier by erosion method. For anti-arthritic potential, 0.1 ml Complete Freund's Adjuvant was injected in the left hind paw of all Wistar rats except normal rats on day 1 and treatment with ENPS at 5, 10, 20, ESC and methotrexate (standard drug) was started at 8th day orally and continued for 21 days. Treatment with methotrexate, ESC, and ENPs revealed a significant reduction of paw edema and pain, restoration of body and immune organ weight, Treatment with ENPs 20 mg/kg remarkably (p < 0.0001) restored serotonin and noradrenaline level, oxidation status, hematological and biochemical parameters with significant down-regulation (p < 0.0001) of IL-6, COX-2, TNF-alpha, NF-κβ whereas, up-regulation of IL-4 and IL-10 in comparison to disease control group as obvious from histological examination of sciatic nerve, liver, and ankle joint. The LD50 of ENPs was more than 2000 mg/kg in the acute toxicity study. The ENPs exhibited anti-inflammatory and anti-arthritic activities especially ENPs at 20 mg/kg.

Rheumatoid arthritis is an autoimmune illness causing deformity, edema, and joint tenderness. Its long-term treatment burdens the healthcare system and leads to toxicity, and thus, finding safe, effective, and affordable therapies is essential. The current study aimed to exhibit the anti-arthritic activity of Carvone-loaded chitosan nanoparticles to treat Freund's complete adjuvant (FCA) arthritis in rats. Healthy albino rats (n = 35) were distributed into seven groups. The 1st group worked as normal control, while the 2nd was arthritic control. The 3rd group received methotrexate (10 mg/kg/week). The 4th group received Carvone (60 mg/kg/day), while the 5th (30 mg/kg/day), 6th (45 mg/kg/day), and 7th (60 mg/kg/day) groups received Carvone-C-NPs, respectively. Nanoparticles, prepared by the ion gelation method, were characterized by zeta size, potential, scanning electron microscopy, and Fourier transform infrared microscopy. NPs have zeta size (78.82 ± 0.02 nm) and potential (19.96 ± 0.02 mV). A significant reduction was shown in paw swelling (5.52 ± 0.05 mm), arthritic score (2.81 ± 0.23), and rheumatoid factor (14.56 ± 0.68 IU/L) by Carvone-C-NPs. qRT-PCR results showed significant down-regulation of pro-inflammatory cytokines [TNF-α (0.25 ± 0.03), IL-1β (0.21 ± 0.06), IL-17a (0.16 ± 0.12), and IL-33 (0.15 ± 0.01)] and up-regulation of anti-inflammatory cytokines [IL-4 (0.85 ± 0.06) and IL-10 (0.66 ± 0.04)] in ankle joint of Carvone-C-NPs treated group. The radiographical and histopathological findings showed reduced pannus formation, joint swelling, and synovial hyperplasia in the Carvone-C-NPs treated group. Overall, it is concluded that Carvone-C-NPs have remarkable anti-arthritic activity and promising anti-inflammatory properties.

Regenerative medicine is an innovative scientific field focused on repairing, replacing, or regenerating damaged tissues and organs to restore their normal functions. A central aspect of this research arena relies on the use of tissue-engineered scaffolds, which serve as structural supports that mimic the extracellular matrix, providing an environment that orchestrates cell growth and tissue formation. Remarkably, the therapeutic efficacy of these scaffolds can be improved by harnessing the properties of other molecules or compounds that have crucial roles in healing and regeneration pathways, such as phytochemicals, enzymes, transcription factors, and non-coding RNAs (ncRNAs). In particular, microRNAs (miRNAs) are a class of tiny (20-24 nt), highly conserved ncRNAs that play a critical role in the regulation of gene expression at the post-transcriptional level. Accordingly, miRNAs are involved in a myriad of biological processes, including cell differentiation, proliferation, and apoptosis, as well as tissue regeneration, angiogenesis, and osteogenesis. On this basis, over the past years, a number of research studies have demonstrated that miRNAs can be integrated into tissue-engineered scaffolds to create advanced therapeutic platforms that precisely modulate cellular behavior and offer a controlled and targeted release of miRNAs to optimize tissue repair and regeneration. Therefore, in this current review, we discuss the most recent advances in the development of miRNA-loaded tissue-engineered scaffolds and provide an overview of the future outlooks that should be aborded in this area of study in order to lay the groundwork for the clinical translation of these tissue engineering approaches.

Photothermal therapy (PTT) and photodynamic therapy (PDT) are potential cancer treatment methods that are minimally invasive with high specificity for malignant cells. Emerging research has concentrated on the application of metal nanoparticles encapsulated in porphyrin and their derivatives to improve the efficacy of these treatments. Gold and silver nanoparticles have distinct optical properties and biocompatibility, which makes them efficient materials for PDT and PTT. Conjugation of these nanoparticles with porphyrin derivatives increases their light absorption and singlet oxygen generation that create a synergistic effect that increases phototoxicity against cancer cells. Porphyrin encapsulation with gold or silver nanoparticles improves their solubility, stability, and targeted tumor delivery. This paper provides comprehensive review on the design, functionalization, and uses of plasmonic silver and gold nanoparticles in biomedicine and how they can be conjugated with porphyrins for synergistic therapeutic effects. Furthermore, it investigates this dual-modal therapy's potential advantages and disadvantages and offers perspectives for future prospects. The possibility of developing gold, silver, and porphyrin nanotechnology-enabled biomedicine for combination therapy is also examined.

Transdermal drug delivery systems are highly appealing as a convenient drug delivery manner applicable to a wide variety of drugs. While most delivery relies on only passive diffusion and suffers low transdermal efficiencies. Ultrasound motivation promotes drug transdermal penetration but still calls for improvement, because only a thin proportion of the ultrasound energy is applied on the drug delivery patch and most ultrasound energy is wasted in deeper portions of biotissues. In this work, we develop a transdermal patch for enhanced drug delivery. The combination of microsized air pockets and the piezoelectric soft structure enable the conversion of an intended proportion of ultrasound energy into electric energy. The intensified drug flow and synergistic ultrasound pressure and electric field function simultaneously to enhance drug transdermal delivery. The delivery efficacy is related to the power of the ultrasound motivation, the size of the microscopic air pockets, and the chemical structure of the drug molecules. The temperature of the patch within the delivery process remains in the safe range, and the mild temperature elevation causes color changes of the thermochromic patch, used to indicate effective ultrasound-patch matching. A model delivery patch for pain release is constructed, and animal experiments indicate that the drug blood concentrations are 100% higher than the delivery using only ultrasound and even more remarkably enhanced when compared to only electric-field-motivated delivery or static delivery without external motivations.

The nuclear receptor-related factor 1 (Nurr1), an orphan nuclear receptor in microglia, has been recognized as a major player in attenuating the transcription of the pro-inflammatory genes to maintain CNS homeostasis. In this study, we investigate Nurr1 trans-repression activity by targeting this receptor with one of the indole derivatives 3-Indole acetic acid hydrazide (IAAH) loaded onto zinc iron oxide (ZnFe2O4) NPs coated with PEG. XRD, SEM, FTIR, UV-Vis spectroscopy, and DLS were used to characterize the synthesized IAAH-NPs. The anti-inflammatory properties of IAAH-NPs on LPS-stimulated SimA9 microglia were assayed by measuring pro-inflammatory cytokine gene expressions and protein levels using RT-PCR and ELISA, respectively. As a result, IAAH-NPs showed an ability to suppress pro-inflammatory genes, including IL-6, IL-1β, and TNF-α in LPS-stimulated SimA9 via targeting Nurr1. The current study suggests that ZnFe2O4 NPs as a delivery system can increase the efficiency of cellular uptake and enhance the IAAH ability to inhibit the pro-inflammatory cytokines. Collectively, we demonstrate that IAAH-NPs is a potential modulator of Nurr1 that combines nanotechnology as a delivery system to suppress neuroinflammation in CNS which opens a window for possible ambitious neuroprotective therapeutic approaches to neuro disorders.

Introduction: Traditional Chinese medicine (TCM) is gaining worldwide popularity as a complementary and alternative medicine. The isolation and characterization of active ingredients from TCM has become optional strategies for drug development. In order to overcome the inherent limitations of these natural products such as poor water solubility and low bioavailability, the combination of nanotechnology with TCM has been explored. Taking advantage of the benefits offered by the nanoscale, various drug delivery systems have been designed to enhance the efficacy of TCM in the treatment and prevention of diseases. Methods: The manuscript aims to present years of research dedicated to the application of nanotechnology in the field of TCM. Results: The manuscript discusses the formulation, characteristics and therapeutic effects of nano-TCM. Additionally, the formation of carrier-free nanomedicines through self-assembly between active ingredients of TCM is summarized. Finally, the paper discusses the safety behind the application of nano-TCM and proposes potential research directions. Discussion: Despite some achievements, the safety of nano-TCM still need special attention. Furthermore, exploring the substance basis of TCM formulas from the perspective of nanotechnology may provide direction for elucidating the scientific intension of TCM formulas.

Overcoming the blood-brain barrier (BBB) remains a significant hurdle in effective drug delivery to the brain. While the BBB serves as a crucial protective barrier, it poses challenges in delivering therapeutic agents to their intended targets within the brain parenchyma. To enhance drug delivery for the treatment of neurological diseases, several delivery technologies to circumvent the BBB have been developed in the last few years. Among them, nanoparticles (NPs) are one of the most versatile and promising tools. Here, we summarize the characteristics of NPs that facilitate BBB penetration, including their size, shape, chemical composition, surface charge, and importantly, their conjugation with various biological or synthetic molecules such as glucose, transferrin, insulin, polyethylene glycol, peptides, and aptamers. Additionally, we discuss the coating of NPs with surfactants. A comprehensive overview of the common in vitro and in vivo models of the BBB for NP penetration studies is also provided. The discussion extends to discussing BBB impairment under pathological conditions and leveraging BBB alterations under pathological conditions to enhance drug delivery. Emphasizing the need for future studies to uncover the inherent therapeutic properties of NPs, the review advocates for their role beyond delivery systems and calls for efforts translating NPs to the clinic as therapeutics. Overall, NPs stand out as a highly promising therapeutic strategy for precise BBB targeting and drug delivery in neurological disorders.

Liposomes (LPs) are a delivery system for stabilizing pharmaceuticals with limited use due to their propensity to congregate and fuse. A proposed method of addressing these problems is polymer coating. In this study, the potential of octadecylamine (ODA)-coated liposomes and carboxymethyl chitosan (CMCS/ODA-LPs) for enhancing Wacao pentacyclic triterpene saponin (WPTS) transport capacity was investigated. CMCS/ODA-LPs were produced by electrostatic adsorption and thin-film hydration. Response surface methodology (RSM) was employed to enhance the process and encapsulation efficiency (EE) for optimum drug encapsulation efficiency. The synthesized WPTS-CMCS/ODA-LPs were uniformly dispersed in a circular shape, and during 14 days of storage at 4 °C, the particle size and morphology did not significantly change. Vesicle size, zeta potential, polydispersity index (PDI), and entrapment efficiency (%) were 179.1 ± 7.31 nm, -29.6 ± 1.35 mV, 0.188 ± 0.052, and 75.62 ± 0.43, respectively. The hemolysis test revealed that WPTS-CMCS/ODA-LPs were sufficiently biocompatible. Compared to WPTS-LPs, WPTS-CMCS/ODA-LPs consistently showed a much more significant cytotoxic effect on cancer cells. Early and WPTS-CMCS/ODA-LPs-induced apoptosis resulted in almost seven times more cell death than the control. Compared to physiological pH 7.3, the pH-sensitive CMCS coupled LPs increased drug release at acidic pH 6.5. These findings suggest the efficacy of pH-sensitive CMCS/ODA-LPs as a medication delivery method for WPTS.

MicroRNAs (miRNAs) are short (18-25 nt), non-coding, widely conserved RNA molecules responsible for regulating gene expression via sequence-specific post-transcriptional mechanisms. Since the human miRNA transcriptome regulates the expression of a number of tumor suppressors and oncogenes, its dysregulation is associated with the clinical onset of different types of cancer. Despite the fact that numerous therapeutic approaches have been designed in recent years to treat cancer, the complexity of the disease manifested by each patient has prevented the development of a highly effective disease management strategy. However, over the past decade, artificial miRNAs (i.e., anti-miRNAs and miRNA mimics) have shown promising results against various cancer types; nevertheless, their targeted delivery could be challenging. Notably, numerous reports have shown that nanotechnology-based delivery of miRNAs can greatly contribute to hindering cancer initiation and development processes, representing an innovative disease-modifying strategy against cancer. Hence, in this review, we evaluate recently developed nanotechnology-based miRNA drug delivery systems for cancer therapeutics and discuss the potential challenges and future directions, such as the promising use of plant-made nanoparticles, phytochemical-mediated modulation of miRNAs, and nanozymes.

Diabetes poses major economic, social, and public health challenges in all countries worldwide. Besides cardiovascular disease and microangiopathy, diabetes is a leading cause of foot ulcers and lower limb amputations. With the continued rise of diabetes prevalence, it is expected that the future burden of diabetes complications, early mortality, and disabilities will increase. The diabetes epidemic is partly caused by the current lack of clinical imaging diagnostic tools, the timely monitoring of insulin secretion and insulin-expressing cell mass (beta (β)-cells), and the lack of patients' adherence to treatment, because some drugs are not tolerated or invasively administrated. In addition to this, there is a lack of efficient topical treatment capable of stopping the progression of disabilities, in particular for treating foot ulcers. In this context, polymer-based nanostructures garnered significant interest due to their tunable physicochemical characteristics, rich diversity, and biocompatibility. This review article emphasizes the last advances and discusses the prospects in the use of polymeric materials as nanocarriers for β-cell imaging and non-invasive drug delivery of insulin and antidiabetic drugs in the management of blood glucose and foot ulcers.

Rheumatoid arthritis (RA) is an inflammatory condition and associated with the symmetrical synovitis of the joints and cause joint pain. The use of anti-rheumatic drugs is associated with many adverse effects. Quercetin, an important polyphenolic flavonoid, possess anti-inflammatory and anti-rheumatic effects. Quercetin use is limited due to poor absorption and bioavailability. Nanomedicines are used for the targeted drug delivery, hence it reduces the adverse effects of the drug. Based upon these factors, quercetin-loaded chitosan nanoparticles (Q-NPs) were prepared by solvent evaporation method, characterized and their better anti-rheumatic effect with mechanistic insights was validated in Freund's complete adjuvant (FCA)-induced arthritic rats along with safety studies. The animals were divided into five groups, each containing 5 animals. Group I was normal control, group II was arthritic control, while groups III, IV and V were administered with quercetin (15 mg/Kg) and Q-NPs (10 and 20 mg/Kg), respectively. The reduction in ankle diameter, serum oxidative stress markers as well as pro- and inflammatory cytokines, e.g., tumor necrosis factor (TNFα), interleukin (IL-6) were determined. The prepared Q-NPs showed hydrodynamic size of 83.9 nm, polydispersity index of 0.687, entrapment efficiency 90.5% as well as no interaction between quercetin and chitosan in Fourier transform infrared spectroscopy (FTIR). A significant reduction (p < 0.001) in ankle diameter was observed after administration of high-dose Q-NPs (4.32 ± 0.14 cm to 5.13 ± 0.62 cm). There was also reduction (p < 0.001) in levels of TNFα and IL-6 following high-dose Q-NPs (72.56 ± 2.30 and 308.19 ± 11.5 pg). The effect on biochemical tests, hematological parameters and oxidative stress parameters was also found to be significant. Histopathological changes of kidney, liver and ankle also confirmed the anti-rheumatic effect of high-dose Q-NPs. The study concludes that administration of Q-NPs (20 mg/Kg) may be used for the treatment of FCA-induced RA in rats.

Cancer is still one of the leading causes of death worldwide. Nanotechnology, particularly nanoparticle-based platforms, is at the leading edge of current cancer management research. Polymer-based nanosystems have piqued the interest of researchers owing to their many benefits over other conventional drug delivery systems. Polymers derived from both natural and synthetic sources have various biomedical applications due to unique qualities like porosity, mechanical strength, biocompatibility, and biodegradability. Polymers such as poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polyethylene glycol (PEG) have been approved by the USFDA and are being researched for drug delivery applications. They have been reported to be potential carriers for drug loading and are used in theranostic applications. In this review, we have primarily focused on the aforementioned polymers and their conjugates. In addition, the therapeutic and diagnostic implications of polymer-based nanosystems have been briefly reviewed. Furthermore, the safety of the developed polymeric formulations is crucial, and we have discussed their biocompatibility in detail. This article also discusses recent developments in block co-polymer-based nanosystems for cancer treatment. The review ends with the challenges of clinical translation of polymer-based nanosystems in drug delivery for cancer therapy.

Although various local anti-inflammatory therapies for ulcerative colitis have been developed, rapid drug elimination from inflamed colitis tissue and off-target side effects reduce their therapeutic efficacy. In this study, we synthesized curcumin (Cur)-loaded hyaluronic acid (HA)-conjugated nanoparticles (Cur-HA-PLGA-NPs) that target inflamed colitis tissue via HA-CD44 interaction with resident colonic epithelial cells and subsequently target activated macrophages for ulcerative colitis therapy. The synthesized spherical Cur-HA-PLGA-NPs showed physicochemical properties similar to those of non-HA-conjugated Cur-PLGA-NPs. HA-PLGA-NPs exhibited selective accumulation in inflamed colitis tissue with minimal accumulation in healthy colon tissue. HA functionalization enhanced targeted drug delivery to intestinal macrophages, significantly increasing HA-PLGA-NP cellular uptake. Importantly, the rectal administration of Cur-HA-PLGA-NPs exhibited better therapeutic efficacy than Cur-PLGA-NPs in animal studies. Histological examination revealed that Cur-HA-PLGA-NPs reduced inflammation with less inflammatory cell infiltration and accelerated recovery with re-epithelialization signs. Our results suggest that Cur-HA-PLGA-NPs are a promising delivery platform for treating ulcerative colitis.

Carriers are equally important as drugs. They can substantially improve bioavailability of cargos and safeguard healthy cells from toxic effects of certain therapeutics. Recently, polymeric nanocarriers (PNCs) have achieved significant success in delivering drugs not only to cells but also to subcellular organelles. Variety of natural sources, availability of different synthetic routes, versatile molecular architectures, exploitable physicochemical properties, biocompatibility, and biodegradability have presented polymers as one of the most desired materials for nanocarrier design. Recent innovative concepts and advances in PNC-associated nanotechnology are providing unprecedented opportunities to engineer nanocarriers and their functions. The efficiency of therapeutic loading has got considerably increased. Structural design-based varieties of PNCs are widely employed for the delivery of small therapeutic molecules to genes, and proteins. PNCs have gained ever-increasing attention and certainly paves the way to develop advanced nanomedicines. This article presents a comprehensive investigation of structural design-based varieties of PNCs and the influences of their physicochemical properties on drug delivery profiles with perspectives highlighting the inevitability of incorporating both the multi-stimuli-responsive and multi-drug delivery properties in a single carrier to design intelligent PNCs as new and emerging research directions in this rapidly developing area.