Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with limited response to conventional chemotherapies such as paclitaxel (PTX) due to poor solubility, low bioavailability, and systemic toxicity. To address these limitations, this study explores mesenchymal stem cell (MSC)-derived exosomes as biocompatible, tumor-homing nanocarriers for PTX delivery. Exosomes were isolated from MSC-conditioned media using ultracentrifugation and tangential flow filtration (TFF), with TFF yielding 8 to 9-fold higher exosome recovery. Flow cytometry confirmed the presence of exosomal (CD63, CD81) and MSC (CD90) surface markers, while transmission electron microscopy and dynamic light scattering revealed spherical vesicles averaging ~160 nm in diameter with a zeta potential of approximately −28 mV. PTX was loaded into exosomes using ultrasonication, achieving an encapsulation efficiency of 31.3 ± 2.0%, and release studies showed an initial burst within 24 h followed by sustained release over 7 days. Blank exosomes exhibited no cytotoxicity toward PANC-1, BxPC-3, and HPNE cells, confirming their excellent biocompatibility. In contrast, PTX-loaded exosomes significantly enhanced cytotoxicity compared to free PTX, reducing IC50 values from 12.48 nM to 7.55 nM in BxPC-3 cells and from 22.44 nM to 19.29 nM in PANC-1 cells and suppressed colony formation and spheroid growth more effectively. These findings demonstrate that MSC-derived exosomes can efficiently encapsulate and deliver PTX, enhancing its antitumor efficacy. This exosome-based platform offers a promising strategy to overcome pharmacological barriers and improve therapeutic outcomes in PDAC.

HIV-associated neurocognitive disorders (HAND) arise from HIV infection of the central nervous system, resulting in chronic neuroinflammation and progressive neuronal damage that impair cognitive, motor, and behavioral functions. Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood-brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND.

Airway remodeling in asthma is characterized by increased extracellular matrix (ECM) production and deposition by airway smooth muscle (ASM) cells. Existing studies have shown contrasting effects of 17β-estradiol (E2) in regulating ASM cellular remodeling via differential activation of estrogen receptors (ERs: α and β). Even though downstream metabolites of E2 (2-hydroxyestradiol: 2-HE and 16-hydroxyestradiol: 16αHE2) are gaining recognition for their biological roles in various cellular systems, their role in ASM remodeling remains largely unexplored. Here, we explore the effects of 2-HE and 16αHE2, a highly potent metabolites, on ECM remodeling in ASM. ECM mRNA's/proteins expression and deposition were determined by Western blotting, qRT-PCR, and In-Cell Western analysis. Interaction of metabolites with ERs was performed using a docking study and their impact on regulation of an estrogen response element (ERE) was monitored via a luciferase reporter assay. Further, the ER-specific effect of metabolites was validated using shRNA-mediated ERα and ERβ knockdown ASM cells. 16αHE2 exposure showed no notable changes in transforming growth factor-β (TGF-β)-induced ECM proteins expression and deposition, whereas 2-HE exposure blunted the TGF-β effects. Molecular docking unveiled the binding of 16αHE2 with ERα, while 2-HE more strongly bound to ERβ, which was also confirmed by ERE-luciferase assay. In ERβ knockdown ASM cells, 2-HE inhibited the TGF-β-induced phosphorylation of SMAD2/3, AKT, and ERK1/2. However, 16αHE2 failed to elicit any of these effects. Furthermore, 2-HE significantly decreased the TGF-β-induced transcriptional activities of AP-1 and NF-κB. Overall, our findings suggest 2-HE blunts TGF-β-induced ECM through ERβ; therefore, it may serve as a novel therapeutic target for airway remodeling and asthma.

Panobinostat is a highly active and potent non-selective histone deacetylase inhibitor (HDACi) that demonstrates significant anticancer activity against various cancers, including pancreatic cancer. However, like other HDAC inhibitors, its anticancer efficacy is often limited due to factors such as hydrophobicity, non-specificity to tumor cells, and poor pharmacokinetics. To overcome these limitations, encapsulating panobinostat in nanocarriers can enhance controlled drug release and increase cellular uptake, thereby improving therapeutic efficacy. In this study, bovine serum albumin (BSA) was utilized as a nanomaterial due to its nontoxicity, biocompatibility, and biodegradability. Initially, various drug-to-polymer ratios were tested to determine the optimal ratio for efficient loading and encapsulation. The BSA nanocarriers were prepared through a self-assembly method, and a drug-to-polymer ratio of 1:2.5 resulted in the highest loading and encapsulation efficiencies of 19.9% and 47.7%, respectively. The hydrodynamic diameter and zeta potential of the optimized nanoparticles were measured at 224.9 ± 5.0 nm and -28.6 ± 0.8 mV, respectively. Results from various physicochemical tests, including FTIR, XRD, DSC, and CD, confirmed the stability of the panobinostat-loaded nanocarriers. In vitro cytotoxicity studies indicated that nanoencapsulation significantly enhanced the anticancer efficacy of panobinostat compared to its free form.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, memory loss, and impairment in daily functioning, making up nearly 60 % of all dementia cases. Current treatments primarily manage symptoms rather than address the disease itself, underscoring the need for more effective solutions. Therapeutic peptides have emerged as promising candidates, targeting critical pathological processes in AD. Additionally, intranasal delivery offers significant advantages, including non-invasiveness, enhanced stability, rapid absorption, and the ability to bypass the blood-brain barrier. This review explores the potential of intranasal peptide delivery for AD treatment, beginning with an overview of the disease's mechanisms and existing therapies. We discuss the challenges of targeting the brain, examine nose-to-brain delivery pathways, and highlight recent advancements in delivery techniques, including the role of nanoparticles in improving efficacy. Our goal is to encourage further research into these innovative delivery strategies that could improve patient compliance and treatment outcomes. While preclinical studies indicate substantial promise, advancing these findings into clinical applications remains crucial to overcoming drug delivery challenges and ensuring long-term safety.

Pancreatic cancer is considered the deadliest among various solid tumors, with a five-year survival rate of 13 %. One of the major challenges in the management of advanced pancreatic cancer is the inefficient delivery of chemotherapeutics to the tumor site. Even though nanocarriers have been developed to improve tumoral delivery of chemotherapeutics, less than 1 % of the drugs reach tumors, rendering inadequate concentration for effective inhibition of tumors. As a potential alternative, mesenchymal stem cells (MSCs) can effectively deliver their cargo to tumor sites because of their resistance to chemotherapeutics and inherent tumor tropism. In this study, we used MSCs for the delivery of dibenzocyclooctyne (DBCO)-functionalized paclitaxel (PTX)-loaded poly (lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA) nanoparticles. MSCs were modified to generate artificial azide groups on their surface, allowing nanoparticle loading via endocytosis and surface conjugation via click chemistry. This dual drug loading strategy significantly improves the PTX-loading capacity of azide-expressed MSCs (MSC-Az, 55.4 pg/cell) compared to unmodified MSCs (28.1 pg/cell). The in vitro studies revealed that PTX-loaded MSC-Az, nano-MSCs, exhibited cytotoxic effects against pancreatic cancer without altering their inherent phenotype, differentiation abilities, and tumor tropism. In an orthotopic pancreatic tumor model, nanoMSCs demonstrated significant inhibition of tumor growth (p < 0.05) and improved survival (p < 0.0001) compared to PTX solution, PTX nanocarriers, and Abraxane. Thus, nano-MSCs could be an effective delivery system for targeted pancreatic cancer chemotherapy and other solid tumors.

Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.

Pancreatic cancer is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 12%. The poor prognosis of pancreatic cancer is primarily attributed to the lack of early detection, the aggressiveness of the disease, and its resistance to conventional chemotherapeutics. The use of combination chemotherapy targeting different key pathways has emerged as a potential strategy to minimize drug resistance while improving therapeutic outcomes. Here, we evaluated a novel approach to treating pancreatic cancer using entinostat (ENT), a selective class I and IV HDAC inhibitor, and oxaliplatin (OXP) administered at considerably lower dosages. Combination therapy exhibited strong synergistic interaction against human (PANC-1) and murine (KPC) pancreatic cancer cells. As expected, ENT treatment enhanced acetylated histone H3 and H4 expression in treated cells, which was even augmented in the presence of OXP. Similarly, cells treated with a combination therapy showed higher expression of cleaved caspase 3 and increased apoptosis compared to monotherapy. To further improve the efficacy of the combination treatment, we encapsulated OXP and ENT into bovine serum albumin and poly(lactic-co-glycolic) acid nanoparticles. Both nanocarriers showed suitable physicochemical properties with respect to size, charge, polydispersity index, and loading. Besides, the combination of OXP and ENT nanoparticles showed similar or even better synergistic effects compared to free drugs during in vitro cytotoxicity and colony formation assays towards pancreatic cancer cells.

Xanthan gum (XG) is an exopolysaccharide synthesized by the aerobic fermentation of simple sugars using Xanthomonas bacteria. It comprises a cellulosic backbone with a trisaccharide side chain connected to alternative glucose residues in the main backbone through α (1→3) linkage. XG dissolves readily in cold and hot water to produce a viscous solution that behaves like a pseudoplastic fluid. It shows excellent resistance to enzymatic degradation and great stability throughout a broad temperature, pH, or salt concentration range. Additionally, XG is nontoxic, biocompatible, and biodegradable, making it a suitable carrier for drug delivery. Furthermore, the carboxylic functions of pyruvate and glucuronic acid offer a considerable opportunity for chemical modification to meet the desired criteria for a specific application. Therefore, XG or its derivatives in conjunction with other polymers have frequently been studied as matrices for tablets, nanoparticles, microparticles, and hydrogels. This review primarily focuses on the applications of XG in various oral delivery systems over the past decade, including sustained-release formulations, gastroretentive dosage forms, and colon-targeted drug delivery. Source, production methods, and physicochemical properties relevant to drug delivery applications of XG have also been discussed.

Central nervous system (CNS) disorders represent one of the leading causes of global health burden. Nonetheless, new therapies approved against these disorders are among the lowest compared to their counterparts. The absence of reliable and efficient in vitro blood–brain barrier (BBB) models resembling in vivo barrier properties stands out as a significant roadblock in developing successful therapy for CNS disorders. Therefore, advancement in the creation of robust and sensitive in vitro BBB models for drug screening might allow us to expedite neurological drug development. This review discusses the major in vitro BBB models developed as of now for exploring the barrier properties of the cerebral vasculature. Our main focus is describing existing in vitro models, including the 2D transwell models covering both single-layer and co-culture models, 3D organoid models, and microfluidic models with their construction, permeability measurement, applications, and limitations. Although microfluidic models are better at recapitulating the in vivo properties of BBB than other models, significant gaps still exist for their use in predicting the performance of neurotherapeutics. However, this comprehensive account of in vitro BBB models can be useful for researchers to create improved models in the future.

Hypertension is a major health concern globally. Elevated blood pressure, initiated and maintained by the brain, is defined as neurogenic hypertension (NH), which accounts for nearly half of all hypertension cases. A significant increase in angiotensin II-mediated sympathetic nervous system activity within the brain is known to be the key driving force behind NH. Blood pressure control in NH has been demonstrated through intracerebrovascular injection of agents that reduce the sympathetic influence on cardiac functions. However, traditional antihypertensive agents lack effective brain permeation, making NH management extremely challenging. Therefore, developing strategies that allow brain-targeted delivery of antihypertensives at the therapeutic level is crucial. Targeting nanotherapeutics have become popular in delivering therapeutics to hard-to-reach regions of the body, including the brain. Despite the frequent use of nanotherapeutics in other pathological conditions such as cancer, their use in hypertension has received very little attention. This review discusses the underlying pathophysiology and current management strategies for NH, as well as the potential role of targeted therapeutics in improving current treatment strategies.

Cancer is one of the most prevalent diseases globally and is the second major cause of death in the United States. Despite the continuous efforts to understand tumor mechanisms and various approaches taken for treatment over decades, no significant improvements have been observed in cancer therapy. Lack of tumor specificity, dose-related toxicity, low bioavailability, and lack of stability of chemotherapeutics are major hindrances to cancer treatment. Nanomedicine has drawn the attention of many researchers due to its potential for tumor-specific delivery while minimizing unwanted side effects. The application of these nanoparticles is not limited to just therapeutic uses; some of them have shown to have extremely promising diagnostic potential. In this review, we describe and compare various types of nanoparticles and their role in advancing cancer treatment. We further highlight various nanoformulations currently approved for cancer therapy as well as under different phases of clinical trials. Finally, we discuss the prospect of nanomedicine in cancer management.

Supplemental data file contains Table S1. Effect of different treatments on complete blood count, Table S2. Effect of different treatments on liver function test, Figure S1. In vitro migratory behavior of the nano-engineered MSCs, and Figure S2. Immunofluorescence staining of A549-luc cells.

Neurodegenerative disorders are primarily characterized by neuron loss. The most common neurodegenerative disorders include Alzheimer’s and Parkinson’s disease. Although there are several medicines currently approved for managing neurodegenerative disorders, a large majority of them only help with associated symptoms. This lack of pathogenesis-targeting therapies is primarily due to the restrictive effects of the blood–brain barrier (BBB), which keeps close to 99% of all “foreign substances” out of the brain. Since their discovery, nanoparticles have been successfully used for targeted delivery into many organs, including the brain. This review briefly describes the pathophysiology of Alzheimer’s, Parkinson’s disease, and amyotrophic lateral sclerosis, and their current management approaches. We then highlight the major challenges of brain-drug delivery, followed by the role of nanotherapeutics for the diagnosis and treatment of various neurological disorders.

Gene therapy encompasses the transfer of exogenous genetic materials into the patient's target cells to treat or prevent diseases. Nevertheless, the transfer of genetic material into desired cells is challenging and often requires specialized tools or delivery systems. For the past 40 years, scientists are mainly pursuing various viruses as gene delivery vectors, and the overall progress has been slow and far from the expectation. As an alternative, nonviral vectors have gained substantial attention due to their several advantages, including superior safety profile, enhanced payload capacity, and stealth abilities. Since nonviral vectors encounter multiple extra- and intracellular barriers limiting the transfer of genetic payload into the target cell nucleus, we have discussed these barriers in detail for this review. A direct approach, utilizing physical methods like electroporation, sonoporation, gene gun, eliminate the requirement for a specific carrier for gene delivery. In contrast, chemical methods of gene transfer exploit natural or synthetic compounds as carriers to increase cellular targeting and gene therapy effectiveness. We have also emphasized the recent advancements aimed at enhancing the current nonviral approaches. Therefore, in this review, we have focused on discussing the current evolving state of nonviral gene delivery systems and their future perspectives.

Biopolymers from various origins have been investigated for biomedical applications due to their biocompatibility, biodegradability, nontoxicity, low cost, and versatility. The development of numerous functionalized biopolymer-based systems with enhanced physicochemical, mechanical, and biological properties further expanded their drug-delivery potential. However, the information related to functionalization techniques, their characterization, and applications of tailor-made biopolymer-based systems is scattered. This chapter summarizes the various topics reviewed by a diverse pool of eminent researchers on the recent development in tailor-made biopolymers designed for drug delivery applications, emphasizing their current status and future perspectives.

Chitosan and its derivatives have been widely explored as polymeric drug carriers in biomedical research due to their biocompatibility, biodegradability, nontoxicity, and low-cost production from renewable resources. At low pH values (i.e., below its pKa of 6.5), the primary amines of chitosan remain positively charged and can spontaneously interact with polyanions to form a polyelectrolyte complex (PEC). The fabrication process of PECs is simple and performed under mild conditions without using any chemical cross-linker, surfactants, or organic solvents. Therefore the chitosan-based PECs are well-tolerated and ideal carriers for the delivery of susceptible drugs and macromolecules. In this chapter, an overview of chitosan, including its general structure, sources, and physicochemical properties, is presented. This chapter also discusses the mechanism of PECs formation, general preparation procedure, and various extrinsic and intrinsic factors affecting the formation and stability of PECs. Finally, the recent developments in chitosan-based PECs and their applications in drug delivery, gene delivery, and tissue engineering are discussed in detail.

The low aqueous solubility and poor stability of drugs under physiological conditions are significant challenges in successful formulation development. Nano-drug delivery systems show great potential to overcome these existing challenges and to eventually enhance the bioavailability of their cargos. Additionally, these nanomedicines offer site-specific and controlled delivery of therapeutic agents. The success of nanotechnology is evident by the number of outstanding nanomedicines currently on the market or in the different phases of clinical trials. Cellulose and its derivatives have gained increasing attention in designing nanomedicines due to their biodegradability, biocompatibility, nontoxicity, and low-cost production from renewable resources. It has several functional groups that can be easily modified to achieve target specificity, pH sensitivity, and sustained action, making them suitable for biomedical applications, particularly in drug delivery. In this book chapter, the source, general physicochemical properties, different structural derivatives of cellulose, and the applications of its nanomaterials in drug delivery are discussed.

The favorable physicochemical properties and excellent safety profile of biopolymers have enabled their extensive applications in biomedical applications, specifically in drug delivery. Smart biopolymers have especially gained a lot of attention because of their programmable drug release capacity in response to specific stimuli or alterations in their surrounding environment. The stimuli-responsive element of these smart biopolymers undergoes structural or conformational changes in response to physical, biological stimuli, or signals that arise from pathological abnormalities, enabling targeting and self-controlled release of therapeutics under desired physiological conditions. Although slow response time to stimulus is one of the major drawbacks of these polymers, fine-tuning can be done using a combinational approach due to their varying adaptability and source of origin. Therefore in this chapter, we have discussed several types of smart polymeric systems, including thermosensitive, pH-sensitive, phase-sensitive, light-sensitive, and bioresponsive polymers. We have also highlighted recent applications of these systems in controlled drug delivery.