<i>In-Silico</i>Validation and Development of Chlorogenic Acid (CGA) Loaded Polymeric Nanoparticle for Targeting Neurodegenerative Disorders

Background: Recent decades witnessed a significant growth in terms of phytocompounds based therapeutics, extensively explored for almost all types of existing disorders. They have also been widely investigated in Neurodegenerative disorders (NDDs) and Chlorogenic acid (CGA), a polyphenolic compound having potential anti-inflammatory and anti-oxidative properties, emerged as a promising compound in ameliorating NDDs. Owing to its poor stability, bioavailability and release kinetics, CGA needed a suitable nanocarrier based pharmaceutical design for targeting NDDs. Objective: The current study is aimed at the in-silico validation of CGA as an effective therapeutic agent targeting various NDDs followed by the fabrication of polymeric nanoparticles-based carrier system to overcome its pharmacological limitations and improve its stability. Methods: A successful in-silico validation using molecular docking techniques along with synthesis of CGA loaded polymeric nanoparticles (CGA-NPs) by ionic gelation method was performed. The statistical optimisation of the developed CGA-NPs was done by Box Behnken method and then the optimized formulation of CGA-NPs was characterised using particle size analysis (PSA), Transmission electron microscopy (TEM), Fourier Transform Infrared spectroscopy (FTIR) along with in-vitro release kinetics analysis. Results & Conclusion: The results attained exhibited average particle size of 101.9 ± 1.5 nm, Polydispersibility (PDI) score of 0.065 and a ZP of −17.4 mV. On a similar note, TEM results showed a size range of CGA-NPs between 90 - 110 nm with a spherical shape of NPs. Also, the data from in-vitro release kinetics showed a sustained release of CGA from the NPs following the first-order kinetics suggesting the appropriate designing of nanoformulation.

Superparticles Formed by Amphiphilic Tadpole-like Single Chain Polymeric Nanoparticles and Their Application as an Ultrasonic Responsive Drug Carrier

Herein, we report self-assembly of tadpole-like single chain polymeric nanoparticles （TPPs） and the ultrasonic response of the resultant superparticles. The TPPs are with an intramolecularly crosslinked poly（2-（methacryloyloxy）ethyl pent-4-ynoate）-rpoly（hydroxyethyl methacrylate） （PMAEP-r-PHEMA） chain as the ＂head＂ and a poly（2- （dimethylamino）ethyl methacrylate （PDMAEMA） linear chain as the ＂tail＂, and are pre- pared simply and emciently by Glaser-coupling of the pendant alkynes in the PMAEP-r- PHEMA block in the common solvent methanol. The formation of the TPPs was confirmed by gel permeation chromatograph, nuclear magnetic resonance spectroscopy, dynamic light scattering, static dynamic scattering, and transmission electron microscopy. In aqueous solution, the amphiphilic TPPs could self-assemble into regular superparticles, driven by aggregation of the hydrophobic ＂heads＂. Since in the structure there is no chain entanglement and the embedding of PDMAEMA chains disturb close-packing of the ＂heads＂, the superpartieles are responsive to a low-energy ultrasonic vibration, as evidenced by greatly enhanced release of the functional molecules from the superparticles by treatment of a low-energy ultrasound. Therefore, the superparticles should be very promising in the use as the drug carriers that can be manipulated from a long distance, considering that ultrasonic energy can be focused at a small area in a relatively long distance from the ultrasound-radiating source.

A Novel CA4P Polymeric Nanoparticle for Murine Hepatoma Therapy

Combretastatin A4 phosphate(CA4P)is a potent vascular disrupting agent with good water solubility.However,it is only effective at high doses,which decreases clinical applicability.Herein,we designed stable CA4P polymeric nanoparticles(CA4P NPs)consisting of various cholesterol derivatives,and with a drug loading efficacy of 93%.The nanoparticles released CA4P in a sustained manner and achieved a 72%inhibition rate in the murine H22 liver tumor model,which was about 2.9-fold higher than that of free CA4P(24.6%).Furthermore,the carrier components of CA4P NPs were metabolized to arginine,cholesterol,ethanol and poly(ethylene glycol)in vivo;therefore,the CA4P NPs are safe and have significant potential for clinical translation.

Responsive Polymeric Nanoparticles for Biofilm-infection Control

With the emergence of multidrug resistance(MDR)in many pathogens,bacterial infections are becoming a growing threat to public health.The frightening scenario is due largely to the formation of biofilms,in which the bacteria are extremely recalcitrant to the conventional antibiotic regimens.To address the emergence of MDR and biofilm-associated infections,numerous polymer-based materials have been designed and prepared recently.The subject of this perspective is the recent development of polymer-based materials that have been applied to combat multidrug-resistant pathogens,to prevent the formation of biofilms,or enhance the eradication efficacy to mature biofilms via killing biofilm-bacteria or dispersing biofilms.The advantages and shortcomings of these polymer-based materials are discussed,as well as the challenges we are facing in the clinical translation of these systems.

On-demand assembly of polymeric nanoparticles for longer-blood-circulation and disassembly in tumor for boosting sonodynamic therapy

Sonodynamic therapy (SDT) is one of the promising strategies for tumor therapy, but its application is usually hindered by fast clearance in blood-circulation, abnormal tumor microenvironment, and inefficient generation of reactive oxygen species. To solve these problems, we proposed an on-demand assembly-disassembly strategy, where the assembly is favorable for longer-blood-circulation and then the disassembly in tumor is favorable for boosting SDT. Hematoporphyrin monomethyl ether (HMME) as the model of organic sonosensitizers were conjugated with hyaluronic acid (HA). Then HA-HMME was mixed with catalase (CAT) and assembled into polymeric nanoparticles (CAT@HA-HMME NPs) with size of ~80 nm. CAT@HA-HMME NPs exhibit good biocompatibility and a longer blood half-time (t1/2 = 4.17 h) which is obviously longer than that (~0.82 h) of HMME molecules. After HA receptor-mediated endocytosis of cancer cells, CAT@HA-HMME NPs can be cleaved by endogenous hyaluronidase, resulting in the on-demand disassembly in tumor to release HA-HMME molecules and CAT. The CAT catalyzes the endogenous H_(2)O_(2) into O_(2) to relieve the hypoxic microenvironment, and the released HA-HMME exhibits a higher ROS generation ability, greatly boosting SDT for the inhibition of tumor growth. Therefore, the on-demand assembly-disassembly strategy may provide some insight in the design and development of nanoagents for tumor therapy.

Platinum-crosslinking polymeric nanoparticle for synergetic chemoradiotherapy of nasopharyngeal carcinoma

Despite extensive use of radiotherapy in nasopharyngeal carcinoma(NPC)treatment because of its high radiosensitivity,there have been huge challenges in further improving therapeutic effect,meanwhile obviously reducing radiation damage.To this end,synergistic chemoradiotherapy has emerged as a potential strategy for highly effective NPC therapy.Here,we developed RGD-targeted platinum-based nanoparticles(RGD-PtNPs,denoted as RPNs)to achieve targeted chemoradiotherapy for NPC.Such nanoparticles consist of an RGD-conjugated shell and a cis-platinum(CDDP)crosslinking core.Taking advantage of RGD,the RPNs may effectively accumulate in tumor,penetrate into tumor tissues and be taken by cancer cells,giving rise to a high delivery efficiency of CDDP.When they are fully enriched in tumor sites,the CDDP loaded RPNs can act as radiotherapy sensitizer and chemotherapy agents.By means of X-ray-promoted tumor cell uptake of nanoparticle and CDDP-induced cell cycle arrest in radiation-sensitive G2/M phases,RPNs may offer remarkable therapeutic outcome in the synergistic chemoradiotherapy for NPC.

Lanthanide-based bulky counterions against aggregation-caused quenching of dyes in fluorescent polymeric nanoparticles

Dye-loaded polymeric nanoparticles(NPs)are promising bioimaging agents because of their available surface chemistry,high brightness,and tunable optical properties.However,high dye loadings can cause the aggregation-caused quenching(ACQ)of the encapsulated fluorophores.Previously,we proposed to mitigate the ACQ inside polymeric NPs by insulating cationic dyes with bulky hydrophobic counterions.In order to implement new functionalities into dye-loaded NPs,here,we extend the concept of bulky counterions to anionic lanthanide-based complexes.We show that by employing Gd-based counterions with octadecyl rhodamine B loaded NPs at 30 wt% versus polymer,the fluorescence quantum yield can be increased to 10-fold(to 0.34).Moreover,Gd-anion provides NPs with enhanced contrast in electron microscopy.A combination of a luminescent Eu-based counterion with a far-red to near-infrared cyanine 5 dye(DiD)yields Forster resonance energy transfer NPs,where the UV-excited Eu-based counterion transfers energy to DiD,generating delayed fluorescence and large stokes shift of -340 nm.Cellular studies reveal low cytotoxicity of NPs and their capacity to internalize without detectable dye leakage,in contrast to leaky NPs with small counterions.Our findings show that the aggregation behavior of cationic dyes in the polymeric NPs can be controlled by bulky lanthanide anions,which will help in developing bright luminescent multifunctional nanomaterials.

Glycyrrhizic Acid-Loaded Poly-ɛ-Caprolactone Nanoparticles Decrease PRRSV Infection in MARC-145 Cells

Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating disease with worldwide distribution caused by Betaarterivirus suid (PRRSV). The virion has great genetic and antigenic variability with a marked increase in virulence. Vaccines tested to date have been of little use in controlling the problems caused by PRRSV, so the present study was conceived to evaluate the antiviral effect of polymeric nanoparticles (PNPs) made with glycyrrhizic acid (GA). Recent work has proven that this nanoparticle system is stable. These nanoparticles have good GA carrying capacity, a size < 250 nm, a spherical morphology, and a wide safety range. The integrity of cell morphology can be maintained for up to 72 h. The antiviral effect of this nanoparticle system was tested in cultures of MARC-145 cells in pre- and coinfection assays with PRRSV to evaluate changes in cell morphology and effects on cell viability. The use of PNPsGA with the real-time quantitative polymerase chain reaction (RT-qPCR) decreased viral infection by 38% in 3 amplification cycles. These results suggest that this system has an antiviral effect against PRRSV under the study conditions established.

Injectable polymeric nanoparticle hydrogel system for long-term anti-inflammatory effect to treat osteoarthritis

Treatment of osteoarthritis(OA)by administration of corticosteroids is a commonly used method in clinics using anti-inflammatory medicine.Oral administration or intra-articular injection of corticosteroids can reduce the pain and progress of cartilage degeneration,but they are usually insufficient to show local and long-term anti-inflammatory effects because of their fast clearance in the body.In this study,we suggest an injectable anti-OA drug depot system for sustained drug release that provides long-term effective therapeutic advantages.Amphiphilic poly(organophosphazene),which has temperature-dependent nanoparticle forming and sol-gel transition behaviors when dissolved in aqueous solution,was synthesized for triamcinolone acetonide(TCA)delivery.Because hydrophobic parts of the polymer can interact with hydrophobic parts of the TCA,the TCA was encapsulated into the self-assembled polymeric nanoparticles.The TCA-encapsulated polymeric nanoparticles(TePNs)were well dispersed in an aqueous solution below room temperature so that they can be easily injected as a sol state into an intra-articular region.However,the TePNs solution transforms immediately to a viscose 3D hydrogel like a synovial fluid in the intra-articular region via the conducted body temperature.An in vitro TCA release study showed sustained TCA release for six weeks.One-time injection of the TePN hydrogel system in an early stage of OA-induced rat model showed a great inhibition effect against further OA progression.The OA-induced knees completely recovered as a healthy cartilage without any abnormal symptoms.

Application of a validated HPLC-PDA method for the determination of melatonin content and its release from poly(lactic acid)nanoparticles

Melatonin is a natural hormone and with the advancement of age its production declines and thereby may result in some neurological disorders. Exogenous administration of melatonin has been suggested as a neuroprotective agent. Due to its low oral bioavailability, the loading of melatonin in polymeric nanoparticles could be an important tool to effectively use exogenous melatonin. The quantification of the incorporated drug within polymeric nanoparticles is an important step in nanoparticles characterization. An analytical method using high performance liquid chromatography equipped with photodiode array detector （HPLC-PDA） was developed and validated for melatonin determination in poly （lactic acid） nanoparticles obtained by a single emulsion-solvent evaporation technique. The melatonin in vitro release profile also was determined by the HPLC method. Mobile phase consisted of acetonitrile： water （65：35, v/v） pumped at a flow rate of 0.9 mL/min, in the isocratic mode and PDA detector was set at 220 nm. The method was validated in terms of the selectivity, linearity, precision, accuracy, robustness, limits of detection and quantification. Analytical curve was linear over the concentration range of 10-100 ~tg/mL, and limits of detection and quantification were 25.9 ng/mL and 78.7 ng/mL, respectively. The mean recovery for melatonin was 100.47% （RSD = 1.25%, n = 9）. In the intra- and inter- assay, the coefficient of variation was less than 2%. Robustness was proved performing changes in mobile phase, column temperature and flow rate. The method was suitable for the determination of melatonin encapsulation efficiency in poly（lactic acid） nanopartieles and for the evaluation of melatonin in vitro release profile.

Nanocarrier-mediated siRNA delivery:a new approach for the treatment of traumatic brain injury-related Alzheimer's disease

Traumatic brain injury and Alzheimer's disease share pathological similarities,including neuronal loss,amyloid-βdeposition,tau hyperphosphorylation,blood-brain barrier dysfunction,neuroinflammation,and cognitive deficits.Furthermore,traumatic brain injury can exacerbate Alzheimer's disease-like pathologies,potentially leading to the development of Alzheimer's disease.Nanocarriers offer a potential solution by facilitating the delive ry of small interfering RNAs across the blood-brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer's disease.U nlike traditional approaches to neuro regeneration,this is a molecula r-targeted strategy,thus avoiding non-specific drug actions.This review focuses on the use of nanocarrier systems for the efficient and precise delive ry of siRNAs,discussing the advantages,challenges,and future directions.In principle,siRNAs have the potential to target all genes and non-targetable protein s,holding significant promise for treating various diseases.Among the various therapeutic approaches currently available for neurological diseases,siRNA gene silencing can precisely"turn off"the expression of any gene at the genetic level,thus radically inhibiting disease progression;however,a significant challenge lies in delivering siRNAs across the blood-brain barrier.Nanoparticles have received increasing attention as an innovative drug delive ry tool fo r the treatment of brain diseases.They are considered a potential therapeutic strategy with the advantages of being able to cross the blood-brain barrier,targeted drug delivery,enhanced drug stability,and multifunctional therapy.The use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective approach.Although this strategy is still in the preclinical exploration stage,it is expected to achieve clinical translation in the future,creating a new field of molecular targeted therapy and precision medicine for the treatment of Alzheimer's disease associated with traumatic brain injury.

RBC Membrane Camouflaged Semiconducting Polymer Nanoparticles for Near-Infrared Photoacoustic Imaging and Photothermal Therapy

Semiconducting conjugated polymer nanoparticles(SPNs)represent an emerging class of phototheranostic materi-als with great promise for cancer treatment.In this report,low-bandgap electron donoracceptor(DA)-conjugated SPNs with sur-face cloaked by red blood cell membrane(RBCM)are developed for highly e ective photoacoustic imaging and photothermal therapy.The resulting RBCM-coated SPN(SPN@RBCM)displays remarkable near-infrared light absorption and good photosta-bility,as well as high photothermal conver-sion e ciency for photoacoustic imaging and photothermal therapy.Particularly,due to the small size(<5 nm),SPN@RBCM has the advantages of deep tumor penetration and rapid clearance from the body with no appreciable toxicity.The RBCM endows the SPNs with prolonged systematic circulation time,less reticuloendothelial system uptake and reduced immune-recognition,hence improving tumor accumulation after intravenous injection,which provides strong photoacoustic signals and exerts excellent photothermal therapeutic e ects.Thus,this work provides a valuable paradigm for safe and highly e cient tumor pho-toacoustic imaging and photothermal therapy for further clinical translation.

Homogeneous PLGA-lipid nanoparticle as a promising oral vaccine delivery system for ovalbumin

In this study,a polymeric lipid nanoparticle(NP)(simplified as Lipid NP)was reported as a promising oral vaccine delivery system.The Lipid NPs composed of a hydrophobic polymeric poly(D,L-lactide-co-glycolide)(PLGA)core and a surface coating of lipid monolayer.Membrane emulsification technique was used to obtain uniform-sized Lipid NPs.Ovalbumin(OVA)was used as a model vaccine.Compared with the pure PLGA NPs,the Lipid NPs achieved higher loading capacity(LC)and entrapment efficiency(EE)for the encapsulated OVA.An in vitro oral release profile showed that the OVA-Lipid NPs were with lower initial burst and could protect the loaded OVA from the harsh gastrointestinal(GI)environment for a long time.In addition,a human microfold cell(M-cell)transcytotic assay demonstrated that due to a lipid layer structure on the particle surface,the Lipid NPs showed higher affinity to the M-cells.Since the M-cell in the intestinal epithelium played an important role in particle transportation as well as intimately associated with the underlying immune cells,the OVA-Lipid NPs effectively induced mucosal and humoral immune responses.

Plugging property and displacement characters of a novel high-temperature resistant polymer nanoparticle

The goal of the research was to investigate the profile control and oil displacement characteristics of the polymer nanoparticles after high temperature swelling.The displacement parameters showed considerable influence on the plugging effect of the high-temperature swelled polymer nanoparticles,such as the core permeability,concentration of nanoparticles in the suspension,swelling time and swelling temperature,which makes it flexible to control the plugging effect by controlling displacement experiments conditions.Experimental results show that polymer nanoparticles dispersion system with a concentration of 500 mg/L is suitable for cores plugging with a permeability of 30×10^(-3)-150×10^(-3)μm^(2),even after aging at 150℃ for three months.The shunt flow experiments show that when the displacement factors are optimal values,the polymer nanoparticles after high temperature swelling to plug the high-permeability layer selectivity and almost do not clog the low-permeability layer.Oil recovery of homogeneous artificial core displacement experiment and a heterogeneous double-tube cores model are increased by 20%and 10.4%on the basis of water flooding.The polymer nanoparticles can be a great help for petroleum engineers to better apply this deep profile control and flooding technology.

Engineered polymer nanoparticles incorporating L-amino acid groups as affinity reagents for fibrinogen

Synthetic polymer hydrogel nanoparticles(NPs)were developed to function as abiotic affinity reagents for fibrinogen.These NPs were made using both temperature-sensitive N-isopropyl acrylamide(NIPAm)and L-amino acid monomers.Five kinds of L-amino acids were acryloylated to obtain functional monomers:L-phenylalanine(Phe)and L-leucine(Leu)with hydrophobic side chains,L-glutamic acid(Glu)with negative charges,and L-lysine(Lys)and L-arginine(Arg)with positive charges.After incubating the NPs with fibrinogen,g-globulin,and human serum albumin(HSA)respectively,the NPs that incorporated Nacryloyl-Arg monomers(AArg@NPs)showed the strongest and most specific binding affinity to fibrinogen,when compared with g-globulin and HSA.Additionally,the fibrinogen-AArg binding model had the best docking scores,and this may be due to the interaction of positively charged AArg@NPs and the negatively charged fibrinogen D domain and the hydrophobic interaction between them.The specific adsorption of AArg@NPs to fibrinogen was also confirmed by the immunoprecipitation assay,as the AArg@NPs selectively trapped the fibrinogen from a human plasma protein mixture.AArg@NPs had a strong selectivity for,and specificity to,fibrinogen and may be developed as a potential human fibrinogen-specific affinity reagent.

Multifunctional conjugated polymer nanoparticles for photoacoustic-based multimodal imaging and cancer photothermal therapy

Photoacoustic imaging(PAI)is a hybrid imaging method based on photoacoustic(PA)effects,which is able to capture the structure,function,and molecular information of biological tissues with high resolution.To date,therapeutic techniques under the guidance of PAI have provided new strategies for accurate diagnosis and precise treatment of tumors.In particular,conjugated polymer nanoparticles have been extensively inspected for PA-based cancer theranostics largely due to their superior optical properties such as tunable spectrum and large absorption coefficient and their good biocompatibility,and abundant functional groups.This mini-review mainly focuses on the recent advances toward the development of novel conjugated polymer nanoparticles for PA-based multimodal imaging and cancer photothermal therapy.

Rational design of biodegradable semiconducting polymer nanoparticles for NIR-II fluorescence imaging-guided photodynamic therapy

Semiconducting polymer nanoparticles(SPNs)have shown great promise in second near-infrared window(NIR-II)phototheranostics.However,the issue of long metabolic time significantly restricts the clinical application of SPNs.In this study,we rationally designed a biodegradable SPN(BSPN50)for NIR-II fluorescence imaging-guided photodynamic therapy(PDT).BSPN50 is prepared by encapsulating a biodegradable SP(BSP50)with an amphiphilic copolymer F-127.BSP50 is composed of NIR-II fluorescent diketopyrrolopyrrole(DPP)segment and degradable poly(phenylenevinylene)(PPV)segment with the ratio of 50/50.BSPN50 has both satisfactory degradability under myeloperoxidase(MPO)/hydrogen peroxide(H_(2)O_(2))and NIR-II fluorescence emission upon 808 nm laser excitation.Furthermore,BSPN50 shows good photodynamic efficacy under 808 nm laser irradiation.BSPN50 shows a faster degradation rate than BSPN100 which has no PPV segment both in vitro and in vivo.In addition,BSPN50 can effectively diagnose tumor via NIR-II fluorescence imaging and inhibit the tumor growth by PDT.Thus,our study provides a rational approach to construct biodegradable nanoplatforms for efficient tumor NIR-II phototheranostics.

Co-delivery of paclitaxel and gemcitabine via folic acid-conjugated polymeric multi-drug nanoparticles (FA-PMDNPs) for the treatment of breast cancer

Multi-drug delivery focuses on different signaling pathways in cancer cells and has synergistic antiproliferative effects.In this manuscript,we developed folic acid(FA)-conjugated polymeric multi-drug nanoparticles(FA-PMDNPs)consisting of poly-L-lysine(PLL)and poly glutamic-conjugated PTX/GEM(PGA-PTX and PGA-GEM)for FA receptor-targeted synergistic breast cancer therapy.The carboxyl-rich structure of PGA provided plenty reaction sites and negative charge for drug loading.Transmission electron microscopy(TEM)results showed that FA-PMDNPs had uniform particle size and spherical morphology.The hemolysis study proved that FA-PMDNPs had good biocompatibility.In vitro cell viability and in vivo studies showed that FA-PMDNPs more effectively inhibited the proliferation of FA receptor(FR)-overexpressing breast cancer cells(4T1)than the pure drugs.Consequently,these results demonstrated that FA-PMDNPs could be effectively targeted at cancer cells compared with free drugs,indicating their strong potential as efficient multi-drug-carrying nano-platforms for cancer treatment.

Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease

Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the severe stages of this disease.While much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic administration.One means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among others.These platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the liver.While many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in ALD.This review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent models.We also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.