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Acute kidney injury (AKI) increases the risk of in-hospital death, adds to expense of care, and risk of early chronic kidney disease. AKI often follows an acute event such that timely treatment could ameliorate AKI and potentially reduce the risk of additional disease. Despite therapeutic success of dexamethasone in animal models, clinical trials have not demonstrated broad success. To improve the safety and efficacy of dexamethasone for AKI, we developed and characterized a novel, kidney-specific nanoparticle enabling specific within-kidney targeting to proximal tubular epithelial cells provided by the megalin ligand cilastatin. Cilastatin and dexamethasone were complexed to H-Dot nanoparticles, which were constructed from generally recognized as safe components. Cilastatin/Dexamethasone/H-Dot nanotherapeutics were found to be stable at plasma pH and demonstrated salutary release kinetics at urine pH. In vivo, they were specifically biodistributed to the kidney and bladder, with 75% recovery in the urine and with reduced systemic toxicity compared to native dexamethasone. Cilastatin complexation conferred proximal tubular epithelial cell specificity within the kidney in vivo and enabled dexamethasone delivery to the proximal tubular epithelial cell nucleus in vitro. The Cilastatin/Dexamethasone/H-Dot nanotherapeutic improved kidney function and reduced kidney cellular injury when administered to male C57BL/6 mice in two translational models of AKI (rhabdomyolysis and bilateral ischemia reperfusion). Thus, our design-based targeting and therapeutic loading of a kidney-specific nanoparticle resulted in preservation of the efficacy of dexamethasone, combined with reduced off-target disposition and toxic effects. Hence, our study illustrates a potential strategy to target AKI and other diseases of the kidney., (Published by Elsevier Inc.)

Due to their inhibition of acetylcholinesterase, organophosphates are among the most toxic of chemicals. Pralidoxime (a.k.a 2-PAM) is the only acetylcholinesterase reactivator approved in the U.S., but 2-PAM only poorly traverses the blood-brain barrier. Previously, we have demonstrated that scL-2PAM, a nanoformulation designed to enter the brain via receptor-mediated transcytosis, is superior to unencapsulated 2-PAM for reactivating brain acetylcholinesterase, ameliorating cholinergic crisis, and improving survival rates for paraoxon-exposed mice. Here, we employ histology and transcriptome analyses to assess the ability of scL-2PAM to prevent neurological sequelae including microglial activation, expression of inflammatory cytokines, and ultimately loss of neurons in mice surviving paraoxon exposures. Levels of the mRNA encoding chemokine ligand 2 (CCL2) were significantly upregulated after paraoxon exposures, with CCL2 mRNA levels in the brain correlating well with the intensity and duration of cholinergic symptoms. Our nanoformulation of 2-PAM was found to be superior to unencapsulated 2-PAM in reducing the levels of the CCL2 transcript. Moreover, brain histology revealed that scL-2PAM was more effective than unencapsulated 2-PAM in preventing microglial activation and the subsequent loss of neurons. Thus, scL-2PAM appears to be a new and improved countermeasure for reducing neuroinflammation and mitigating brain damage in survivors of organophosphate exposures.

The burgeoning global mortality rates attributed to cancer have precipitated a critical reassessment of conventional therapeutic modalities, most notably chemotherapy, due to their pronounced adverse effects. This reassessment has instigated a paradigmatic shift towards nanomedicine, with a particular emphasis on the potentialities of biopolymer-assisted drug delivery systems. Biopolymers, distinguished by their impeccable biocompatibility, versatility, and intrinsic biomimetic properties, are rapidly ascending as formidable vectors within the cancer theragnostic arena. This review endeavors to meticulously dissect the avant-garde methodologies central to biopolymer-based nanomedicine, exploring their synthesis, functional mechanisms, and subsequent clinical ramifications. A key focus of this analysis is the pioneering roles and efficacies of lipid-based, polysaccharide, and composite nano-carriers in enhancing drug delivery, notably amplifying the enhanced permeation and retention effect. This examination is further enriched by referencing flagship nano formulations that have received FDA endorsement, thereby underscoring the transformative potential and clinical viability of biopolymer-based nanomedicines. Furthermore, this discourse illuminates groundbreaking advancements in the realm of photodynamic therapy and elucidates the implications of advanced imaging techniques in live models. Conclusively, this review not only synthesizes current research trajectories but also delineates visionary pathways for the integration of cutting-edge biomaterials in cancer treatment. It charts a course for future explorations within the dynamic domain of biopolymer-nanomedicine, thereby contributing to a deeper understanding and enhanced application of these novel therapeutic strategies., Competing Interests: The author reports no conflicts of interest in this work., (© 2024 Alharbi.)

Cellular senescence is a significant contributor to intervertebral disc aging and degeneration. However, the application of senotherapies, such as senomorphics targeting senescence markers and the senescence-associated secretory phenotype (SASP), remains limited due to challenges in precise delivery. Given that the natural killer group 2D (NKG2D) ligands are increased on the surface of senescent nucleus pulposus (NP) cells, the NKG2D-overexpressing NP cell membranes (NNPm) are constructed, which is expected to achieve a dual targeting effect toward senescent NP cells based on homologous membrane fusion and the NKG2D-mediated immunosurveillance mechanism. Then, mesoporous silica nanoparticles carrying a peroxisome proliferator-activated receptor-ɣ coactivator 1α (PGC1α)inducer (SP) are coated with NNPm (SP@NNPm) and it is found that SP@NNPm selectively targets senescent NP cells, and the SP cores exhibit pH-responsive drug release. Moreover, SP@NNPm effectively induces PGC1α-mediated mitochondrial biogenesis and mitigates senescence-associated markers induced by oxidative stress and the SASP, thereby alleviating puncture-induced senescence and disc degeneration. This dual-targeting nanotherapeutic system represents a novel approach to delivery senomorphics for disc degeneration treatment., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly conserved self-degradation process, has received considerable attention as an emerging therapeutic target for cancer. With the rapid development of nanomedicine, nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance. Hence, considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy, we outline the latest advances in autophagy-based nanotherapeutics. Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression, the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated. Further, emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways, including modulation of the mammalian target of rapamycin (mTOR) pathway, autophagy-related (ATG) and its complex expression, reactive oxygen species (ROS) and mitophagy, interference with autophagosome-lysosome fusion, and inhibition of hypoxia-mediated autophagy. In addition, combination therapies in which nano-autophagy modulation is combined with chemotherapy, phototherapy, and immunotherapy are also described. Finally, the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned., (© 2024 The Authors.)

Extracellular vesicles (EVs) are cell-secreted nanovesicles that play an important role in long-range cell-cell communication. Although EVs pose a promising alternative to cell-based therapy, targeted in vivo delivery still falls short. Many studies have explored the surface modification of EVs to enhance their targeting capabilities. However, to our knowledge, there are no standardized practices to confirm the successful surface modification of EVs or calculate the degree of conjugation on EV surfaces (conjugation efficiency). These pieces of information are essential in the reproducibility of targeted EV therapeutics and the determination of optimized conjugation conditions for EVs to see significant therapeutic effects in vitro and in vivo. This review will discuss the vast array of techniques adopted, technologies developed, and efficiency definitions made by studies that have calculated EV/nanoparticle surface conjugation efficiency and how differences between studies may contribute to differently reported conjugation efficiencies.

Intrinsic drug resistance mechanisms of tumor cells often reduce intracellular drug concentration to suboptimal levels. Epithelial-to-mesenchymal transition (EMT) is a pivotal process in tumor progression and metastasis that confers an aggressive phenotype as well as resistance to chemotherapeutics. Therefore, it is imperative to develop novel strategies and identify new targets to improve the overall efficacy of cancer treatment. We developed SN38 (active metabolite of irinotecan)-assembled glycol chitosan nanoparticles (cSN38) for the treatment of pancreatic ductal adenocarcinoma (PDAC). Furthermore, cSN38 and the TGF-β1 inhibitor LY364947 formed composite nanoparticles upon self-assembly (cSN38 + LY), which obviated the poor aqueous solubility of LY364947 and enhanced drug sensitivity. The therapeutic efficacy of cSN38 + LY nanotherapeutics was studied in vitro and in vivo using suitable models. The cSN38 nanoparticles exhibited an antitumor effect that was significantly attenuated by TGF-β-induced EMT. The cellular uptake of SN38 was impeded during EMT, which affected the therapeutic efficacy. The combination of LY364947 and cSN38 markedly enhanced the cellular uptake of SN38, increased cytotoxic effects, and inhibited EMT in PDAC cells in vitro. Furthermore, cSN38 + LY significantly inhibited PDAC xenograft growth in vivo. The cSN38 + LY nanoparticles increased the therapeutic efficacy of cSN38 via repressing the EMT of PDAC cells. Our findings provide a rationale for designing nanoscale therapeutics to combat PDAC., (© 2023 Federation of European Biochemical Societies.)

Ferrocene-based nanoparticles have garnered interest as reactive oxygen species (ROS)-responsive nanocarriers of anticancer drugs and imaging agents. However, their biomedical applications remain limited due to their poor physiological stability. PEGylation of nanocarriers improves their stability and biocompatibility. In this study, we aimed to develop novel PEG-ferrocene nanoparticles (PFNPs) with enhanced stability and ROS responsiveness for the delivery of paclitaxel (PTX) and imaging agents. PEGylation improved the stability of ferrocene nanoparticles, inhibiting their ROS-responsive destruction. Several PEG-ferrocene polymers containing different molar ratios of methacrylic acid and poly (ethylene glycol) methyl ether methacrylate was designed for optimization. ROS-responsive polymers with optimal monomer ratios were self-assembled into PFNPs with enhanced stability. The PFNPs distended, effectively releasing encapsulated PTX and imaging agents within 8 h in the presence of ROS. Furthermore, they remained stable, with no changes in their hydrodynamic diameters or polydispersity indexes after storage in an aqueous solution and biological buffer. The accumulation of PFNPs in a tumor model in vivo was 15-fold higher than a free dye. PTX-loaded PFNPs showed a substantial tumor-suppression effect, reducing tumor size to approximately 18% of that in the corresponding control group. These findings suggest a promising application of ROS-responsive PFNPs in tumor treatment as biocompatible nanocarriers of anticancer drugs and imaging agents., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Extracellular vesicles (EVs) are nanoscale bilayer phospholipid membrane vesicles released by cells. Contained large molecules such as nucleic acid, protein, and lipid, EVs are an integral part of cell communication. The contents of EVs vary based on the cell source and play an important role in both pathological and physiological conditions. EVs can be used as drugs or targets in disease treatment, and changes in the contents of EVs can indicate the progression of diseases. In recent years, with the continuous exploration of the structure, characteristics, and functions of EVs, the potential of engineered EVs for drug delivery and therapy being constantly explored. This review provides a brief overview of the structure, characteristics and functions of EVs, summarizes the advanced application of EVs and outlook on the prospect of it. It is our hope that this review will increase understanding of the current development of medical applications of EVs and help us overcome future challenges., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Zhang et al.)

Neurodegeneration is characterized by progressive, disabling, and incurable neurological disorders with the massive loss of specific neurons. As one of the most promising potential therapeutic strategies for neurodegenerative diseases, stem cell therapy exerts beneficial effects through different mechanisms, such as direct replacement of damaged or lost cells, secretion of neurotrophic and growth factors, decreased neuroinflammation, and activation of endogenous stem cells. However, poor survival and differentiation rates of transplanted stem cells, insufficient homing ability, and difficulty tracking after transplantation limit their further clinical use. The rapid development of nanotechnology provides many promising nanomaterials for biomedical applications, which already have many applications in neurodegenerative disease treatment and seem to be able to compensate for some of the deficiencies in stem cell therapy, such as transport of stem cells/genes/drugs, regulating stem cell differentiation, and real-time tracking in stem cell therapy. Therefore, nanotherapeutic strategies combined with stem cell therapy is a promising therapeutic approach to treating neurodegenerative diseases. The present review systematically summarizes recent advances in stem cell therapeutics and nanotherapeutic strategies and highlights how they can be combined to improve therapeutic efficacy for the treatment of neurodegenerative diseases., Competing Interests: The authors declare no conflict of interest., (© 2023 Wei et al.)

Hypoxia, a common characteristic of bacterial infections, is known to be closely associated with the emergence of multidrug-resistant bacteria, which hastens the need to develop advanced microbicides and antibacterial techniques. Photodynamic therapy is a promising strategy to reduce bacterial antibiotic resistance and employs photosensitizers, excitation light sources, and sufficient oxygen to generate toxic reactive oxygen species (ROS). The inherent limitation of PDT is that the generation of ROS is restricted by the hypoxic microenvironment in infection sites. Here, an oxygen self-supplying nanotherapeutic is developed to enhance antibacterial activity against multidrug-resistant bacteria on the basis of fluorinated boron dipyrromethene (BODIPY)-based glycomimetics. The nanotherapeutic not only could capture the bacteria efficiently but also was able to act as an oxygen carrier to relieve the hypoxic microenvironment of bacterial infections, thus achieving enhanced PDT efficacy. In a Pseudomonas aeruginosa infection of a rat cornea, typical administration of the nanotherapeutic decreased the infiltrate and showed a faster healing capacity in comparison with BODIPY-based glycomimetics. Self-supplying oxygen nanotherapeutics that relieve the hypoxic microenvironment and interfere with bacterial colonization have been shown to be a promising candidate for the management of drug-resistant microbial keratitis.

Acute kidney injury (AKI) is a serious kidney disease without specific medications currently except for expensive dialysis treatment. Some potential drugs are limited due to their high hydrophobicity, poor in vivo stability, low bioavailability and possible adverse effects. Besides, kidney-targeted drugs are not common and small molecules are cleared too quickly to achieve effective drug concentrations in injured kidneys. These problems limit the development of pharmacological therapy for AKI. Nanotherapeutics based on nanotechnology have been proved to be an emerging and promising treatment strategy for AKI, which may solve the pharmacological therapy dilemma. More and more nanotherapeutics with different physicochemical properties are developed to efficiently deliver drugs, increase accumulation and control release of drugs in injury kidneys and also directly as effective antioxidants. Here, we discuss the recent nanotherapeutics applied in the treatment and prevention of AKI with improved effectiveness and few side effects., Competing Interests: The authors report no conflicts of interest., (© 2020 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

The ongoing opioid crisis highlighted the need for non-steroidal anti-inflammatory drugs (NSAIDs), nonaddictive analgesics against pain, fever, and inflammation. However, NSAIDs may cause gastrointestinal and cardiovascular adverse effects. To avoid systemic toxicity and deliver drugs to diseased tissues, nanotechnology methods of NSAID encapsulation have been reported and some have reached clinical development. Currently, 57 micro- and nanodrugs are approved by the US FDA. Already approved nanoanalgesics have revealed superior efficacy or reduced toxicity compared with placebo or lower doses of systemically administered active comparators. In this review, the evidence for approval of the marketed nanodrugs will be discussed, with a focus on therapies for pain and inflammation. Nanomedicine remains an attractive field for the development of targeted analgesics., Competing Interests: Declaration of interests The authors have no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glioblastoma (GB) is an aggressive cancer with high microvascular proliferation, resulting in accelerated invasion and diffused infiltration into the surrounding brain tissues with very low survival rates. Treatment options are often multimodal, such as surgical resection with concurrent radiotherapy and chemotherapy. The development of resistance of tumor cells to radiation in the areas of hypoxia decreases the efficiency of such treatments. Additionally, the difficulty of ensuring drugs effectively cross the natural blood-brain barrier (BBB) substantially reduces treatment efficiency. These conditions concomitantly limit the efficacy of standard chemotherapeutic agents available for GB. Indeed, there is an urgent need of a multifunctional drug vehicle system that has potential to transport anticancer drugs efficiently to the target and can successfully cross the BBB. In this review, we summarize some nanoparticle (NP)-based therapeutics attached to GB cells with antigens and membrane receptors for site-directed drug targeting. Such multicore drug delivery systems are potentially biodegradable, site-directed, nontoxic to normal cells and offer long-lasting therapeutic effects against brain cancer. These models could have better therapeutic potential for GB as well as efficient drug delivery reaching the tumor milieu. The goal of this article is to provide key considerations and a better understanding of the development of nanotherapeutics with good targetability and better tolerability in the fight against GB.

Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline. Existing drugs only suppress symptoms or delay further deterioration but do not address the cause of the disease. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates, such as acetylcholinesterase inhibitors, are currently utilized as an effective clinical therapy. Currently, nano-based therapies can make a difference, providing new therapeutic options by helping drugs to cross the blood-brain barrier and enter the brain more effectively. The main aim of this review was to highlight advances in research on the development of nano-based therapeutics for improved treatment of AD.

Liver cancer, being the utmost prevalent fatal malignancy worldwide, is ranked as the fifth leading cause of deaths associated with cancer. Patients with liver cancer are diagnosed often at an advanced stage, contributing to poor prognosis. Of all forms of liver cancer, hepatocellular carcinoma (HCC) contributes to 90% of cases, with chemotherapy being the treatment of choice. However, unfavorable toxicity of chemotherapy drugs and the vulnerability of nucleic acid-based drugs to degradation, have limited their application in clinical settings. So, in order to improvise their therapeutic efficacy in HCC treatment, various nanocarrier drug delivery systems have been explored. Furthermore, nanoparticle based imaging provides valuable means of accurately diagnosing HCC. Thus, in recent years, the advent of nanomedicine has shown great potential and progress in dramatically altering the approach to the diagnosis as well as treatment of liver cancer. Nanoparticles (NPs) are being explored as potential drug carriers for small molecules, miRNAs, and therapeutic genes used for liver cancer treatment. This review emphasizes on the current developments and applications of nanomedicine based therapeutic and diagnostic approaches in HCC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Orally targeted delivery of anti-inflammatory drugs to macrophages has attracted great attention for minimizing the symptoms of ulcerative colitis (UC). In this investigation, we encapsulated curcumin (CUR) into polymeric nanoparticles (NPs), and conjugated chondroitin sulfate (CS) to their surfaces. The resulting CS-NPs had an average diameter of 281 nm, monodisperse size distribution and negatively charged surface. Cell experiments indicated that these NPs showed excellent biocompatibility, and yielded significantly higher cell internalization efficiency in Raw 264.7 macrophages than their counterparts (carboxymethyl cellulose-functionalized CUR-encapsulated NPs, CUL-NPs). Moreover, CS-NPs exhibited a dramatically stronger capacity to inhibit the secretion of the major pro-inflammatory cytokines from lipopolysaccharide-stimulated macrophages compared with CUL-NPs. In vivo experiments revealed that oral administration of chitosan/alginate hydrogel embedding CS-NPs achieved better therapeutic outcomes against UC comparied with CUL-NPs. Collectively, our results demonstrated that CS-NP-embedded hydrogel held a great promise to be developed as a macrophage-targeted drug delivery system for UC treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Spherical nucleic acids (SNAs), an emerging class of gene-regulatory nanotherapeutics, typically consist of a nanoparticle core densely functionalized with a shell of radially oriented small interfering RNA (siRNA) oligonucleotides, microRNA (miRNA) mimics, or antagonists. The unique three-dimensional SNA structure regardless of core type (e.g., gold or lipids) confers heightened resistance to nuclease-mediated degradation and accounts for robust cell entry in the absence of auxiliary transfection vehicles. In murine models of glioblastoma (GBM), the most aggressive and prevalent form of malignant brain cancers, systemically administered siRNA or miRNA-conjugated SNAs penetrated blood-brain and blood-tumor barriers and robustly reduced tumor progression. Here, we describe methods for the synthesis and physicochemical and biological characterization of SNA gene silencing effects in glioma cells in vitro and in patient-derived xenograft models in vivo.

Inflammatory bowel disease (IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy, and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting, sustained drug release, and decreased adverse effects. Here, we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition, the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment., Competing Interests: Conflict-of-interest statement: The authors declared no conflict of interest related to this study.