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Delivering therapeutic agents efficiently to inflamed regions remains an intractable challenge following myocardial ischemia-reperfusion injury (MI/RI) due to the transient nature of the enhanced permeability and retention effect, which disappears after 24 h. Leveraging the inflammation-homing and plasticity properties of circulating monocytes (MN) as hitchhiking carriers and further inducing their polarization into anti-inflammatory phenotype macrophages upon reaching the inflamed sites is beneficial for MI/RI therapy. Herein, DSS/PB@BSP nanoparticles capable of clearing reactive oxygen species and inhibiting inflammation were developed by employing hollow Prussian blue nanoparticles (PB) as carriers to encapsulate betamethasone sodium phosphate (BSP) and further modified with dextran sulfate sodium (DSS), a targeting ligand for the scavenger receptor on MN. This formulation was internalized into MN as living cell drug depots, reprogramming them into anti-inflammation type macrophages to inhibit inflammation. In vitro assessments revealed the successful construction of the nanoparticle. In a murine MI/RI model, circulating MN laden with these nanoparticles significantly enhanced drug delivery and accumulation at the cardiac injury site, exhibiting favorable therapeutic ability and promoting M2-biased differentiation. Our study provides an effective approach with minimally invasion and biosecurity that makes this nanoplatform as a promising candidate for immunotherapy and clinical translation in the treatment of MI/RI., Competing Interests: Declaration of competing interest The author reports no conflicts of interest in this work., (Copyright © 2024. Published by Elsevier B.V.)

Herein, we reported novel docetaxel-decorated solid lipid nanoparticle (DCT-SLN)-loaded dual thermoreversible system (DCT-DRTS) for intramuscular administration with reduced burst effect, sustained release and improved antitumor efficacy. The optimized DCT-DRTs was subjected to in-vitro and in-vivo analyses. Antitumor evaluation of the DCT-DRTS was executed and compared with DCT-hydrogel, and DCT-suspension trailed by the histopathological and immune-histochemical analyses. The DCT-SLN gave a mean particle size of 157 nm and entrapment efficiency of 93 %. It was a solid at room temperature, and changed to liquid at physiological temperature due to its melting point of about 32 °C. Unlikely, poloxamer mixture remained liquefied at 25-27 °C, however converted to gel at physiological temperature. This behavior demonstrated opposed reversible property of the DCT-SLN and poloxamer hydrogel in DCT-DRTS system, making it ideal for intramuscular administration and quick gelation inside the body. The DCT-DRTS sustained the drugs release and unlike DCT-hydrogel, the preliminary plasma concentration of DCT-DRTS was significantly reduced, overcoming the burst release. A meaningfully enhanced antitumor efficacy and improved survival rate was observed from DCT-DRTS in tumor cell xenograft athymic nude mice. Additionally, increased apoptotic and reduced proliferation markers were observed in DCT-DRTS treated tumor masses. It was concluded that DCT-DRTS may be a suitable choice for intramuscular administration of DCT with sustained release, improved bioavailability, reduced toxicity and enhanced antitumor effects., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In addition to the solubilization of poorly water-soluble, highly lipophilic drugs, lipid nanoemulsions bear potential for drug targeting approaches. This requires that the drug remains within the emulsion droplets until they reach the site of action. Since drug release is rather controlled by the lipophilicity of the drug than by the formulation, this study systematically investigated the influence of drug lipophilicity on the course of drug transfer in (physiological) acceptor media. An increase in drug lipophilicity, according to ClogD/P values, was achieved by the formation of lipophilic prodrugs of 5-phenylanthranilic acid - a potential pathoblocker. The range of substances was supplemented by orlistat, lumefantrine and cholesteryl acetate as model drugs. Drug transfer from supercooled trimyristin nanodroplets was determined via differential scanning calorimetry by monitoring their onset crystallization temperature, which decreases linearly with increasing drug content. Release of the model (pro)drugs ranged from burst to hardly any release in the order of the ClogD/P values. Except for cholesteryl acetate, the results were in line with the lipophilicity of the model (pro)drugs estimated by their retention times on a reversed-phase HPLC column under isocratic conditions. An approximate prediction of drug release kinetics was, thus, possible by logP calculations and, to a limited extent, also by reversed-phase HPLC. A further finding was the increased drug loading capacity of the lipid nanoemulsion for lipophilic prodrugs, if the structural changes of the parent compound were accompanied by a lower melting point., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Antimicrobial resistance is considered one of the biggest threats to public health worldwide. Methicillin-resistant S. aureus is the causative agent of a number of infections and lung colonization in people suffering from cystic fibrosis. Moreover, a growing body of evidence links the microbiome to the development of cancer, as well as to the success of the treatment. In this view, the development of novel antibiotics is of critical importance, and SV7, a novel antibiotic active against MRSA at low concentrations, represents a promising candidate. However, the low aqueous solubility of SV7 hampers its therapeutic translation. In this study, SV7 was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to improve the solubility profile, to ensure sustained release and eventually support deposition in the airways. Furthermore, PLGA NPs were formulated as dry powder to extend their shelf-life and were shown to efficiently target intracellular infections. After identifying a formulation with suitable physico-chemical characteristics, SV7-loaded NPs were investigated in vitro in terms of inhibitory activity against MRSA, and their safety profile in lung epithelial cells. Subsequently, the activity against MRSA intracellular infections was investigated in a co-culture model of MRSA and macrophages. To test the translatability of our findings, SV7-loaded NPs were tested in vivo in a Galleria mellonella infection model. In conclusion, SV7-loaded NPs showed a safe profile and efficient inhibitory activity against MRSA at low concentrations. Furthermore, their activity against intracellular infections was confirmed, and was retained in vivo, rendering them a promising candidate for treatment of MRSA lung infections., Competing Interests: Declaration of competing interest Olivia Merkel is a Scientific Board Member for Coriolis Pharma GmbH, AMW GmbH and Carver Biosciences and an Advisor for PARI Pharma GmbH, Boehringer-Ingelheim International GmbH, Corden Pharma, and AbbVie Deutschland GmbH on unrelated projects., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers. We focus on fingolimod, a small molecule drug that is FDA-approved for treatment of multiple sclerosis, which has also shown promise in the treatment of stroke. Unfortunately, fingolimod has poor solubility and very extensive partitioning to plasma proteins and RBCs (in whole blood, 86% partitions to RBCs, 13.96% to plasma proteins, and 0.04% is free). We develop a liposomal formulation that slows the partitioning of fingolimod to RBCs and plasma proteins, enables intravenous delivery, and additionally prevents fingolimod toxicity to RBCs. The liposomal formulation nearly completely prevented fingolimod adsorption to plasma proteins (association with plasma proteins was 98.4 ± 0.4% for the free drug vs. 5.6 ± 0.4% for liposome-loaded drug). When incubated with whole blood in vitro, the liposomal formulation greatly slowed partitioning of fingolimod to RBCs and also eliminated deleterious effects of fingolimod on RBC rigidity, morphology, and hemolysis. In vivo, the liposomal formulation delayed fingolimod partitioning to RBCs for over 30 min, a critical time window for stroke. Fingolimod-loaded liposomes showed improved efficacy in a mouse model of post-stroke neuroinflammation, completely sealing the leaky blood-brain barrier (114 ± 11.5% reduction in albumin leak into the brain for targeted liposomes vs. 38 ± 16.5% reduction for free drug). This effect was only seen for liposomes modified with antibodies to enable targeted delivery to the site of action, and not in unmodified, long-circulating liposomes. Thus, loading fingolimod into liposomes prevented partitioning to RBCs and associated toxicities and enabled targeted delivery. This paradigm can be used for tuning the blood distribution of small molecule drugs for the treatment of acute illnesses requiring rapid pharmacologic intervention., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Clinical guidelines for infectious keratitis treatment require that anti-inflammatory drugs can only be used after infection elimination, which causes irreversible inflammatory damage to the cornea. In this work, photodynamic metal organic frameworks (PCN-224) were used as drug carrier to load Pt NPs with catalase-like activity and anti-inflammatory drug (Dexamethasone, DXMS) for endogenous oxygen generation and reduced corneal damage, respectively. The photodynamic therapy (PDT) effect was greatly enhanced in bacteria elimination and bacterial biofilms removal through catalysis of overexpressed hydrogen peroxide (H 2 O 2 , ∼8.0 and 31.0 μM in bacterial solution and biofilms, respectively) into oxygen by Pt NPs. More importantly, the cationic liposome modified PCN-224@Pt@DXMS@Liposomes (PPDL NPs) greatly enhanced the adhesion to negatively charged ocular surface and penetration into corneal barrier and bacterial biofilms. Both in vitro cell viability test and in vivo eye irritation tests proved good biocompatibility of PPDL NPs under 660 nm laser irradiation. Furthermore, PDT of PPDL NPs in rapid bacteria killing was verified through infectious keratitis animal model. The superior bactericidal effect of antibacterial materials could largely replace the bactericidal effect of the immune system. It is worth mentioning that this simultaneous sterilization and anti-inflammation treatment mode is a new exploration against the clinical treatment guidelines., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent decades, there has been a burgeoning interest in cell membrane coating strategies as innovative approach for targeted delivery systems in biomedical applications. Platelet membrane-coated nanoparticles (PNPs), in particular, are gaining interest as a new route for targeted therapy due to their advantages over conventional drug therapies. Their stepwise approach blends the capabilities of the natural platelet membrane (PM) with the adaptable nature of manufactured nanomaterials, resulting in a synergistic combination that enhances drug delivery and enables the development of innovative therapeutics. In this context, we present an overview of the latest advancements in designing PNPs with various structures tailored for precise drug delivery. Initially, we describe the types, preparation methods, delivery mechanisms, and specific advantages of PNPs. Next, we focus on three critical applications of PNPs in diseases: vascular disease therapy, cancer treatment, and management of infectious diseases. This review presents our knowledge of PNPs, summarizes their advancements in targeted therapies and discusses the promising potential for clinical translation of PNPs., (Copyright © 2023. Published by Elsevier B.V.)

Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w/w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to -25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Precisely co-delivering antigens and immunosuppressants via nano/microcarriers to antigen-presenting cells (APCs) to induce antigen-specific immune tolerance represents a highly promising strategy for treating or preventing autoimmune diseases. The physicochemical properties of nano/microcarriers play a pivotal role in regulating immune function, with particle size and surface charge emerging as crucial parameters. In particular, very few studies have investigated micron-scale carriers of antigens. Herein, various nanoparticles and microparticles (NPs/MPs) with diverse particle sizes (ranging from 200 nm to 5 μm) and surface charges were prepared. Antigen peptides (MOG35-55) and immunosuppressants were encapsulated in these particles to induce antigen-specific immune tolerance. Two emulsifiers, PVA and PEMA, were employed to confer different surface charges to the NPs/MPs. The in vitro and in vivo studies demonstrated that NP/MP-PEMA could induce immune tolerance earlier than NP/MP-PVA and that NP/MP-PVA could induce immune tolerance more slowly and sustainably, indicating that highly negatively charged particles can induce immune tolerance more rapidly. Among the different sizes and charged particles tested, 200-nm-NP-PVA and 3-μm-MP-PEMA induced the greatest immune tolerance. In addition, the combination of NPs with MPs can further improve the induction of immune tolerance. In particular, combining 200 nm-NP-PVA with 3 μm-MP-PEMA or combining 500 nm-NP-PEMA with 3 μm-MP-PVA had optimal therapeutic efficacy. This study offers a new perspective for treating diseases by combining NPs with MPs and applying different emulsifiers to prepare NPs and MPs., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 μm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD., Competing Interests: Declaration of competing interest The nor-LAAM-MP technology described in this publication has been filed as a patent application through Virginia Commonwealth University (VCU). Qingguo Xu, Matthew Banks, Diane Ingabire, Chaolong Qin, Tuo Meng, and Aji Alex Moothedathu Raynold are the co-inventors who are subject to certain rules and restrictions under VCU policy. The terms of this arrangement are being managed by VCU in accordance with its conflict-of-interest policies., (Copyright © 2023. Published by Elsevier B.V.)

Achieving precise control of nanoparticle size while maintaining consistency and high uniformity is of paramount importance for improving the efficacy of nanoparticle-based therapies and minimizing potential side effects. Although microfluidic technologies are widely used for reliable nanoparticle synthesis, they face challenges in meeting critical homogeneity requirements, mainly due to imperfect mixing efficiency. Furthermore, channel clogging during continuous operation presents a significant obstacle in terms of quality control, as it progressively impedes the mixing behavior necessary for consistent nanoparticle production for therapeutic delivery and complicates the scaling-up process. This study entailed the development of a 3D-printed novel micromixer embedded with hemispherical baffle microstructures, a dual vortex mixer (DVM), which integrates Dean vortices to generate two symmetrical counter-rotating intensified secondary flows. The DVM with a relatively large mixer volume showed rapid mixing characteristics even at a flow rate of several mL min -1 and produced highly uniform lipids, liposomes, and polymer nanoparticles in a size range (50-130 nm) and polydispersity index (PDI) values below 0.15. For the evaluation of products, SARS-CoV-2 Spike mRNA-loaded lipid nanoparticles were examined to verify protein expression in vitro and in vivo using firefly luciferase (FLuc) mRNA. This showed that the performance of the system is comparable to that of a commercial toroidal mixer. Moreover, the vigorous in-situ dispersion of nanoparticles by harnessing the power of vortex physically minimizes the occurrence of aggregation, ensuring consistent production performance without internal clogging of a half-day operation and facilitating quality control of the nanoparticles at desired scales., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer is a serious threat to human health because of its high annual mortality rate. It has attracted significant attention in healthcare, and identifying effective strategies for the treatment and relief of cancer pain requires urgency. Drug delivery systems (DDSs) offer the advantages of excellent efficacy, low cost, and low toxicity for targeting drugs to tumor sites. In recent decades, copolymer carriers based on poly(phenylalanine) (PPhe) and poly(3,4-dihydroxy-L-phenylalanine) (PDopa) have been extensively investigated owing to their good biocompatibility, biodegradability, and controllable stimulus responsiveness, which have resulted in DDSs with loading and targeted delivery capabilities. In this review, we introduce the synthesis of PPhe and PDopa, highlighting the latest proposed synthetic routes and comparing the differences in drug delivery between PPhe and PDopa. Subsequently, we summarize the various applications of PPhe and PDopa in nanoscale-targeted DDSs, providing a comprehensive analysis of the drug release behavior based on different stimulus-responsive carriers using these two materials. In the end, we discuss the challenges and prospects of polypeptide-based DDSs in the field of cancer therapy, aiming to promote their further development to meet the growing demands for treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant potential in therapeutic applications for treating alopecia areata; however, the systemic adverse effects of oral administration and low absorption rate at the target site limit its application. Hence, to address this issue, we designed topical formulations of tofacitinib-loaded cationic lipid nanoparticles (TFB-cNLPs) with particle sizes of approximately 200 nm. TFB-cNLPs promoted percutaneous absorption and hair follicle targeting in an ex vivo pig ear model. TFB-cNLP decreased IFN-γ-induced alopecia areata symptoms in an in vitro follicle model by blocking the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. It also reduced the number of CD8 + NKG2D + T cells in a C3H mouse model of alopecia areata in vivo, thereby inhibiting the progression of alopecia areata and reversing hair loss. These findings suggest that TFB-cNLP enhanced hair follicle targeting and has the potential for topical treatment or prevention of alopecia areata., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanoparticles fabricated to deliver anticancer drugs are usually designed to present optimized tumor penetration and cell internalization. However, there are some barriers and difficulties with most current technologies. Herein, size and charge switchable polyamidoamine (PAMAM) megamers (SChPMs) were prepared for the delivery of doxorubicin (DOX). SChPMs were fabricated by connecting PAMAM dendrimers with pH-sensitive bonds and surface PEGylation. At pH 7.4, the size and surface charge of these nanocarriers were approximately 100 nm and + 0.75 mV, but at the acidic extracellular pH of tumor cells (pH 6.5), their size were reduced dramatically (15 nm) and their surface charge increased to +6.7 mV. Cell studies confirmed that alteration of the size and surface charge enhanced their penetration into multicellular spheroids and cell internalization. These megamers, in addition to delivering the drug to the deeper areas of the tumor, could powerfully overcome physiological resistance to anthracycline-based drugs. The nanocarrier revealed enhanced antitumoral activity in animal studies. Toxicology studies and histopathological assessments of vital tissues of 4 T1 tumor bearing mice indicated minimal tissue damage when DOX-loaded SChPMs (DSChPMs) were used. It can be concluded that the versatile and agile nanocarriers developed in this study could be considered for further investigations into their clinical application., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Poly(ethylene glycol) (PEG) is widely utilized as a hydrophilic coating to extend the circulation time and improve the tumor accumulation of polymeric micelles. Nonetheless, PEGylated micelles often activate complement proteins, leading to accelerated blood clearance and negatively impacting drug efficacy and safety. Here, we have crafted amphiphilic block copolymers that merge hydrophilic sulfoxide-containing polymers (psulfoxides) with the hydrophobic drug 7-ethyl-10-hydroxylcamptothecin (SN38) into drug-conjugate micelles. Our findings show that the specific variant, PMSEA-PSN38 micelles, remarkably reduce protein fouling, prolong blood circulation, and improve intratumoral accumulation, culminating in significantly increased anti-cancer efficacy compared with PEG-PSN38 counterpart. Additionally, PMSEA-PSN38 micelles effectively inhibit complement activation, mitigate leukocyte uptake, and attenuate hyperactivation of inflammatory cells, diminishing their ability to stimulate tumor metastasis and cause inflammation. As a result, PMSEA-PSN38 micelles show exceptional promise in the realm of anti-metastasis and significantly abate SN38-induced intestinal toxicity. This study underscores the promising role of psulfoxides as viable PEG substitutes in the design of polymeric micelles for efficacious anti-cancer drug delivery., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Nanoparticles have a great potential to significantly improve the delivery of therapeutics to the brain and may also be equipped with properties to investigate brain function. The brain, being a highly complex organ shielded by selective barriers, requires its own specialized detection system. However, a significant hurdle to achieve these goals is still the identification of individual nanoparticles within the brain with sufficient cellular, subcellular, and temporal resolution. This review aims to provide a comprehensive summary of the current knowledge on detection systems for tracking nanoparticles across the blood-brain barrier and within the brain. We discuss commonly employed in vivo and ex vivo nanoparticle identification and quantification methods, as well as various imaging modalities able to detect nanoparticles in the brain. Advantages and weaknesses of these modalities as well as the biological factors that must be considered when interpreting results obtained through nanotechnologies are summarized. Finally, we critically evaluate the prevailing limitations of existing technologies and explore potential solutions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. During the preparation of this work, the authors used ChatGPT (Version 3.5) in order to reduce the word count of this review. After using this tool, the authors reviewed and edited the content., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Preventing the recurrence of melanoma after surgery and accelerating wound healing are among the most challenging aspects of melanoma management. Photothermal therapy has been widely used to treat tumors and bacterial infections and promote wound healing. Owing to its efficacy and specificity, it may be used for postoperative management of tumors. However, its use is limited by the uncontrollable distribution of photosensitizers and the likelihood of damage to the surrounding normal tissue. Hydrogels provide a moist environment with strong biocompatibility and adhesion for wound healing owing to their highly hydrophilic three-dimensional network structure. In addition, these materials serve as excellent drug carriers for tumor treatment and wound healing. It is possible to combine the advantages of both of these agents through different loading modalities to provide a powerful platform for the prevention of tumor recurrence and wound healing. This review summarizes the design strategies, research progress and mechanism of action of hydrogels used in photothermal therapy and discusses their role in preventing tumor recurrence and accelerating wound healing. These findings provide valuable insights into the postoperative management of melanoma and may guide the development of promising multifunctional hydrogels for photothermal therapy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors β1 (TGF-β1), Smad3 and inflammatory cytokines IL-6, IL-1β and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (μ 3  - OH, and - OH 2 ) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done., (Copyright © 2024. Published by Elsevier B.V.)

Cisplatin (CDDP), as a broad-spectrum anticancer drug, is able to bind to DNA and inhibit cell division. Despite the widespread use of cisplatin since its discovery, cisplatin resistance developed during prolonged chemotherapy, similar to other small molecule chemotherapeutic agents, severely limits its clinical application. Cisplatin resistance in cancer cells is mainly caused by three reasons: DNA repair, decreased cisplatin uptake/increased efflux, and cisplatin inactivation. In earlier combination therapies, the emergence of multidrug resistance (MDR) in cancer cells prevented the achievement of the desired therapeutic effect even with the accurate combination of two chemotherapeutic drugs. Therefore, combination therapy using nanocarriers for co-delivery of drugs is considered to be ideal for alleviating cisplatin resistance and reducing cisplatin-related toxicity in cancer cells. This article provides an overview of the design of cisplatin nano-drugs used to combat cancer cell resistance, elucidates the mechanisms of action of cisplatin and the pathways through which cancer cells develop resistance, and finally discusses the design of drugs and related carriers that can synergistically reduce cancer resistance when combined with cisplatin., (Copyright © 2023. Published by Elsevier B.V.)

As an essential branch of targeted drug delivery, oral targeted delivery is attracting growing attention in recent years. In addition to site-specific delivery for the treatment of locoregional diseases in the gastrointestinal tract (GIT), oral targeted delivery to remote sites beyond the GIT emerges as a cutting-edge research topic. This review aims to provide an overview of the fundamental concepts and most recent advances in this field. Owing to the physiological barriers existing in the GIT, carrier systems should be transported across the enteric epithelia to target remote sites. Recently, pioneer investigations have validated the transport of intact micro- or nanocarriers across gastrointestinal barriers and subsequently to various distal organs and tissues. The microfold (M) cell pathway is the leading mechanism underlying the oral absorption of particulates, but the contribution of the transcellular and paracellular pathways should not be neglected either. In addition to well-acknowledged physicochemical and biological factors, the formation of a protein corona may also influence the biological fate of carrier systems. Although in an early stage of conceptualization, oral targeted delivery to remote diseases has demonstrated promising potential for the treatment of inflammation, tumors, and diseases inflicting the lymphatic and mononuclear phagocytosis systems., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The spontaneous healing of critical-sized bone defects is often limited, posing an increased risk of complications and suboptimal outcomes. Osteogenesis, a complex process central to bone formation, relies significantly on the pivotal role of osteoblasts. Despite the well-established osteogenic properties of vitamin D 3 (VD 3 ), its lipophilic nature confines administration to oral or muscle injection routes. Therefore, a strategic therapeutic approach involves designing a multifunctional carrier to enhance efficacy, potentially incorporating it into the delivery system. Here, we introduce an innovative sterosome-based delivery system, utilizing palmitic acid (PA) and VD 3 , aimed at promoting osteogenic differentiation and facilitating post-defect bone regeneration. The delivery system exhibited robust physical characteristics, including excellent stability, loading efficiency, sustained drug release and high cellular uptake efficiency. Furthermore, comprehensive investigations demonstrated outstanding biocompatibility and osteogenic potential in both 2D and 3D in vitro settings. A critical-sized calvarial defect model in mice recapitulated the notable osteogenic effects of the sterosomes in vivo. Collectively, our research proposes a clinically applicable strategy for bone healing, leveraging PA/VD 3 sterosomes as an efficient carrier to deliver VD 3 and enhance bone regenerative effects., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Tumor heterogeneity and drug resistance have been invincible features of cancer for its complete cure. Despite the advent of immunotherapy, the expansion and diversification of cancer cells evolved even in the absence or presence of drug treatment discourage additional therapeutic interventions. For the eradication of cancer cells, therefore, an 'all-at-once' strategy is required, which exploits both target-selective chemotherapy and non-selective physicotherapy. Multifactorial microcapsules comprising gold nanoparticles (AuNPs) and a self-assembly protein of α-synuclein (αS) were fabricated, in which hydrophobic and hydrophilic drugs could be separately encapsulated by employing lipid-based inverted micelles (IMs). Their combined physico-chemical therapeutic effects were examined since they also contained both membrane-disrupting IMs and heat-generating AuNPs upon irradiation as physicotherapeutic agents. For the optimal enclosure of IMs containing hydrophilic drugs, a porous inner skeleton made of poly(lactic-co-glycolic acid) was introduced, which would play the roles of not only compartmentalizing the internal space but also enhancing proteolytic disintegration of the microcapsules to discharge and stabilize IMs to the outside. In fact, hydrophobic paclitaxel and hydrophilic doxorubicin showed markedly enhanced drug efficacy when delivered in the IM-containing microcapsules exhibiting the 'quantal' release of both drugs into the cells whose integrity could be also affected by the IMs. In addition, the remnants of αS-AuNP microcapsules produced via proteolysis also caused cell death through photothermal effect. The multifactorial microcapsules are therefore considered as a promising anti-cancer drug carrier capable of performing combinatorial selective and non-selective chemical and physical therapies to overcome tumor heterogeneity and drug resistance., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 μm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 μm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9-10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare., Competing Interests: Declaration of competing interest Nanologica AB (Södertälje) is a biotech company manufacturing porous silica particles for chromatography and drug delivery applications. Iconovo AB (Medicon Village, Lund) develops inhalation products, inhaler devices and dry powder formulation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H 2 O 2 )-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H 2 O 2 , characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H 2 O 2 . In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent., (Copyright © 2023. Published by Elsevier B.V.)

Neurotrophic growth factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) have been considered as potential therapeutic candidates for neurodegenerative disorders due to their important role in modulating the growth and survival of neurons. However, clinical translation remains elusive, as their large size hinders translocation across the blood-brain barrier (BBB), and their short half-life in vivo necessitates repeated administrations. Local delivery to the brain offers a potential route to the target site but requires a suitable drug-delivery system capable of releasing these proteins in a controlled and sustained manner. Herein, we develop a cryogel microcarrier delivery system which takes advantage of the heparin-binding properties of GDNF and BDNF, to reversibly bind/release these growth factors via electrostatic interactions. Droplet microfluidics and subzero temperature polymerization was used to create monodisperse cryogels with varying degrees of negative charge and an average diameter of 20 μm. By tailoring the inclusion of 3-sulfopropyl acrylate (SPA) as a negatively charged moiety, the release duration of these two growth factors could be adjusted to range from weeks to half a year. 80% SPA cryogels and 20% SPA cryogels were selected to load GDNF and BDNF respectively, for the subsequent biological studies. Cell culture studies demonstrated that these cryogel microcarriers were cytocompatible with neuronal and microglial cell lines, as well as primary neural cultures. Furthermore, in vivo studies confirmed their biocompatibility after administration into the brain, as well as their ability to deliver, retain and release GDNF and BDNF in the striatum. Overall, this study highlights the potential of using cryogel microcarriers for long-term delivery of neurotrophic growth factors to the brain for neurodegenerative disorder therapeutics., Competing Interests: Declaration of competing interest The authors declare that there are no competing financial interests., (Copyright © 2023. Published by Elsevier B.V.)

Immunotherapy is currently a standard of care in the treatment of many malignancies. However, predictable side effects caused by systemic administration of highly immunostimulatory molecules have been a serious concern within this field. Intratumoural expression or silencing of immunogenic and immunoinhibitory molecules using nucleic acid-based approaches such as plasmid DNA (pDNA) and small interfering RNA (siRNA), respectively, could represent a next generation of cancer immunotherapy. Here, we employed lipid nanoparticles (LNPs) to deliver either non-specific pDNA and siRNA, or constructs targeting two prominent immunotherapeutic targets OX40L and indoleamine 2,3-dioxygenase-1 (IDO), to tumours in vivo. In the B16F10 mouse model, intratumoural delivery of LNP-formulated non-specific pDNA and siRNA led to strong local immune activation and tumour growth inhibition even at low doses due to the pDNA immunogenic nature. Replacement of these non-specific constructs by pOX40L and siIDO resulted in more prominent immune activation as evidenced by increased immune cell infiltration in tumours and tumour-draining lymph nodes. Consistently, pOX40L alone or in combination with siIDO could prolong overall survival, resulting in complete tumour regression and the formation of immunological memory in tumour rechallenge models. Our results suggest that intratumoural administration of LNP-formulated pDNA and siRNA offers a promising approach for cancer immunotherapy., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2023. Published by Elsevier B.V.)

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior., Competing Interests: Declaration of competing interest Jan Kubanek is a co-inventor on a pending patent., (Copyright © 2023. Published by Elsevier B.V.)

Despite their great versatility and ease of functionalization, most polymer-based nanocarriers intended for use in drug delivery often face serious limitations that can prevent their clinical translation, such as uncontrolled drug release and off-target toxicity, which mainly originate from the burst release phenomenon. In addition, residual solvents from the formulation process can induce toxicity, alter the physico-chemical and biological properties and can strongly impair further pharmaceutical development. To address these issues, we report polymer prodrug nanoparticles, which are prepared without organic solvents via an all-aqueous formulation process, and provide sustained drug release. This was achieved by the "drug-initiated" synthesis of well-defined copolymer prodrugs exhibiting a lower critical solution temperature (LCST) and based on the anticancer drug gemcitabine (Gem). After screening for different structural parameters, prodrugs based on amphiphilic diblock copolymers were formulated into stable nanoparticles by all-aqueous nanoprecipitation, with rather narrow particle size distribution and average diameters in the 50-80 nm range. They exhibited sustained Gem release in human serum and acetate buffer, rapid cellular uptake and significant cytotoxicity on A549 and Mia PaCa-2 cancer cells. We also demonstrated the versatility of this approach by formulating Gem-based polymer prodrug nanoparticles loaded with doxorubicin (Dox) for combination therapy. The dual-drug nanoparticles exhibited sustained release of Gem in human serum and acidic release of Dox under accelerated pathophysiological conditions. Importantly, they also induced a synergistic effect on triple-negative breast cancer line MDA-MB-231, which is a relevant cell line to this combination., (Copyright © 2023. Published by Elsevier B.V.)

A bioactive compound, collagen peptide (CP), is widely used for biological activities such as anti-photoaging and antioxidant effects, with increased oral bioavailability because of its low molecular weight and high hydrophilicity. However, controlling release time and increasing retention time in the digestive tract for a more convenient oral administration is still a challenge. We developed CP-loaded chitosan (CS) microcapsules via strong and rapid ionic gelation using a highly negative phytic acid (PA) crosslinker. The platform enhanced the oral bioavailability of CP with controlled gastrointestinal delivery by utilizing the mucoadhesiveness and tight junction-opening properties of CS. CS and CP concentrations varied from 1.5 to 3.5% and 0-30%, respectively, for optimal and stable microcapsule synthesis. The physicochemical properties, in vitro release profile with intestinal permeability, in vivo oral bioavailability, in vivo biodistribution, anti-photoaging effect, and antioxidant effect of optimized CS microcapsules were analyzed to investigate the impact of controlling parameters. The structure of CS microcapsules was tuned by PA diffused gradient ionic cross-linking degree, resulting in a controlled CP release region in the gastrointestinal tract. The optimized microcapsules increased C max , AUC, and t max by 1.5-, 3.4-, and 8.0-fold, respectively. Furthermore, CP in microcapsules showed anti-photoaging effects by downregulating matrix metalloproteinases-1 via antioxidant effects. According to our knowledge, this is the first study to microencapsulate CP for oral bioavailability enhancement. The peptide delivery method employed is simple, economical, and can be applied to customize bioactive compound administration., Competing Interests: Declaration of Competing Interest There are no competing interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

Nanoparticle (NP) formulations are inherently polydisperse making their structural characterization and justification of specifications complex. It is essential, however, to gain an understanding of the physico-chemical properties that drive performance in vivo. To elucidate these properties, drug-containing poly(lactic acid) (PLA)-poly(ethylene glycol) (PEG) block polymeric NP formulations (or PNPs) were sub-divided into discrete size fractions and analyzed using a combination of advanced techniques, namely cryogenic transmission electron microscopy, small-angle neutron and X-ray scattering, nuclear magnetic resonance, and hard-energy X-ray photoelectron spectroscopy. Together, these techniques revealed a uniquely detailed picture of PNP size, surface structure, internal molecular architecture and the preferred site(s) of incorporation of the hydrophobic drug, AZD5991, properties which cannot be accessed via conventional characterization methodologies. Within the PNP size distribution, it was shown that the smallest PNPs contained significantly less drug than their larger sized counterparts, reducing overall drug loading, while PNP molecular architecture was critical in understanding the nature of in vitro drug release. The effect of PNP size and structure on drug biodistribution was determined by administrating selected PNP size fractions to mice, with the smaller sized NP fractions increasing the total drug-plasma concentration area under the curve and reducing drug concentrations in liver and spleen, due to greater avoidance of the reticuloendothelial system. In contrast, administration of unfractionated PNPs, containing a large population of NPs with extremely low drug load, did not significantly impact the drug's pharmacokinetic behavior - a significant result for nanomedicine development where a uniform formulation is usually an important driver. We also demonstrate how, in this study, it is not practicable to validate the bioanalytical methodology for drug released in vivo due to the NP formulation properties, a process which is applicable for most small molecule-releasing nanomedicines. In conclusion, this work details a strategy for determining the effect of formulation variability on in vivo performance, thereby informing the translation of PNPs, and other NPs, from the laboratory to the clinic., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Herein, we synthesized a lipid-mimicking organic material (PCD&#95;FA) that can surpass the efficacy of lipid-based nanoparticles and demonstrated its potential as a delivery vehicle for various hydrophilic drugs. PCD&#95;FA is a conjugate of pH-sensitive carbon dots (PCDs) and fatty acids (FAs) and has potential applications in several fields owing to various combinations of carbon dots (CDs) and FAs. Similar to phospholipids, PCD-FAs have hydrophilic heads and hydrophobic tails that allow them to self-form nanoparticles (Coposomes) in the aqueous phase. Coposomes can easily combine various hydrophilic head and hydrophobic tail combinations, and several drugs can be encapsulated, or drug release patterns can be controlled according to each property. We analyzed the differences in size, drug loading efficiency, and drug release patterns of Coposomes depending on the type of FAs and characteristics of the encapsulated drugs. Additionally, cell entry and intracellular drug release mechanisms of the Coposomes were identified. The applicability of Coposomes as drug delivery carriers for tumor treatment has been demonstrated in comparison with that of liposomes formulation in tumor-bearing mouse models. Consequently, this study presents possibilities for the synthesis and application of various amphiphilic lipid-mimicking organic materials via the combination of CDs and FAs with various functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Currently, commercially available antibody therapies must be delivered via parenteral administration. Oral delivery of antibodies could increase patient compliance and improve quality of life, however there is currently no viable system for delivering antibodies orally. In this work, a self-assembled, pH-responsive nanoparticle delivery system was developed to load and deliver antibodies via the oral route. The nanoparticles were synthesized via nanoprecipitation using the pH-responsive copolymers based on poly(methacrylic acid-co-methyl methacrylate)-block-poly(ethylene glycol). The reversibly hydrophobic nature of this polymer allowed it to function as an antibody delivery system via self-assembly. Characteristics of the polymer, including monomer ratios and molecular weight, as well as parameters of the nanoprecipitation process were optimized using Design of Experiments to achieve nanoparticles with desired size, polydispersity, loading efficiency, and release characteristics. Ultimately, the synthesized and optimized nanoparticles exhibited a hydrodynamic size within a range that avoids premature clearance, a low polydispersity index, and high IgG loading efficiency. In in vitro antibody release studies at physiologically relevant pH values, the nanoparticles exhibit promising release profiles. The nanoparticles presented in this work show potential as oral delivery vehicles for therapeutic antibodies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Various attributes of micelles, such as PEG density and particle size, are considered to be related to blood clearance. The structural stability of micelles is another key attribute that will affect the in vivo fate. This study employed fluorescence resonance energy transfer (FRET) analysis to guide the preparation of polymeric micelles with different structural stability. Micelles prepared using copolymers with longer hydrophobic blocks showed higher structural stability; emulsification was a better method than nanoprecipitation to prepare stable micelles. The fast chain exchange kinetics and the high-water content of micellar cores explained the low structural stability of those micelles. Moreover, this study highlighted the importance of structural stability that affected blood clearance in concert with PEG length and particle size. One-third of the small and stable micelles were detected in the blood 24 h after injection. While unstable micelles would be cleared from the circulation within 4 h. Notably, there would be a threshold of structural stability. Micelles with structural stability below this threshold were quickly cleared even if they possessed a longer PEG length and a smaller size. In contrast, higher structural stability allowed polymeric micelles to maintain higher integrity in vivo and enhance tumor accumulation and anti-tumor efficacy. In conclusion, this study systematically analyzed the importance of the structural stability of micelles on the in vivo fate., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Combination chemotherapeutic drugs administered via a single nanocarrier for cancer treatment provides benefits in reducing dose-limiting toxicities, improving the pharmacokinetic properties of the cargo and achieving spatial-temporal synchronization of drug exposure for maximized synergistic therapeutic effects. In an attempt to develop such a multi-drug carrier, our work focuses on functional multimodal polypeptide-based polymeric nanogels (NGs). Diblock copolymers poly (ethylene glycol)-b-poly (glutamic acid) (PEG-b-PGlu) modified with phenylalanine (Phe) were successfully synthesized and characterized. Self-assembly behavior of the resulting polymers was utilized for the synthesis of NGs with hydrophobic domains in cross-linked polyion cores coated with inert PEG chains. The resulting NGs were small (ca. 70 nm in diameter) and were able to encapsulate the combination of drugs with different physicochemical properties such as cisplatin and neratinib. Drug combination-loaded NGs exerted a selective synergistic cytotoxicity towards EGFR overexpressing ovarian cancer cells. Moreover, we developed ligand-installed EGFR-targeted NGs and tested them as an EGFR-overexpressing tumor-specific delivery system. Both in vitro and in vivo, ligand-installed NGs displayed preferential associations with EGFR (+) tumor cells. Ligand-installed NGs carrying cisplatin and neratinib significantly improved the treatment response of ovarian cancer xenografts. We also confirmed the importance of simultaneous administration of the dual drug combination via a single NG system which provides more therapeutic benefit than individual drug-loaded NGs administered at equivalent doses. This work illustrates the potential of our carrier system to mediate efficient delivery of a drug combination to treat EGFR overexpressing cancers., (Copyright © 2023 Elsevier B.V. All rights reserved.)

There has been growing discovery and use of therapeutic peptides in drug delivery and tissue engineering. Peptides are smaller than proteins and can be formulated into drug delivery systems without significant loss of their bioactivity, which remains a concern with proteins. However, the smaller size of peptides has made the controlled release of these bioactive molecules from carriers challenging. Thus, there has been increasing development of carriers to improve the controlled release of peptides by leveraging hydrophobic and electrostatic interactions between the peptide and the carrier. The focus of this review paper is to critically discuss synthetic and natural nanoparticles and microparticles that have been investigated for the controlled delivery of peptides with emphasis on the underlying interactions., (Copyright © 2023. Published by Elsevier B.V.)

The clinical application of EDV, a potent antioxidant drug approved for amyotrophic lateral sclerosis (ALS), is limited by its short biological half-life and poor water solubility necessitating hospitalization during intravenous infusion. Nanotechnology-based drug delivery constitutes a powerful tool through inferring drug stability and targeted drug delivery improving drug bioavailability at the diseased site. Nose-to-brain drug delivery offers direct access to the brain bypassing the blood brain barrier and reducing systemic biodistribution. In this study, we designed EDV-loaded poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles (NP-EDV) for intranasal administration. NPs were formulated by the nanoprecipitation method. Morphology, EDV loading, physicochemical properties, shelf-life stability, in vitro release and pharmacokinetic assessment in mice were conducted. EDV was efficiently loaded into ∼90 nm NPs, stable up to 30 days of storage, at ∼3% drug loading. NP-EDV reduced H 2 O 2 -induced oxidative stress toxicity in mouse microglial cell line BV-2. Optical imaging and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed that intranasal delivery of NP-EDV offered higher and more sustained brain uptake of EDV compared to intravenous administration. This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited to two clinically approved drugs only., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dendritic cells (DCs), the primary antigen-presenting cells in the immune system, play a critical role in regulating tumor immune responses. However, the tumor immunosuppressive microenvironment severely impedes the process of antigen-presenting and DC maturation, thereby limiting the efficacy of cancer immunotherapy. In this work, a pH-responsive polymer nanocarrier (PAG) modified with aminoguanidine (AG) was constructed for the efficient delivery of bortezomib (BTZ) through bidentate hydrogen bonds and electrostatic adsorption formed between guanidine groups of PAG and boronic acid groups of BTZ. The obtained PAG/BTZ nanoparticles exhibited pH-responsive release of BTZ and AG in the acidic tumor microenvironment. On the one hand, BTZ induced potent immune activation by eliciting immunogenic cell death (ICD) and releasing damage-associated molecular patterns. On the other hand, the cationic AG significantly promoted antigen uptake by DCs and activated DC maturation. As a result, PAG/BTZ significantly stimulated tumoral infiltration of cytotoxic T lymphocytes (CTLs) and triggered robust antitumor immune responses. Thus, it showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Biofilm-associated infections (BAI) have posed serious threats to public health. Novel therapy based on carbon monoxide (CO) is being increasingly appreciated. However, CO therapy like inhaled gas treatment was impeded owing to its low bioavailability. Besides, the direct use of CO releasing molecules (CORM) showed low therapeutic efficacy in BAI. Therefore, it is vital to improve the efficiency of CO therapy. Herein, we proposed polymeric CO releasing micelles (pCORM) from self-assembly of amphiphilic copolymers containing CORM bearing block as hydrophobic part and acryloylmorpholine block as hydrophilic part. The catechol modified CORM were conjugated through pH cleavable boronate ester bonds and releasing CO passively under biofilm microenvironment. When combined with subminimal inhibitory concentration antibiotic amikacin, pCORM could significantly enhance its bactericidal efficiency against biofilm-encapsulated multidrug-resistant bacteria, representing a promising approach to combat BAI., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The facile availability of nanoformulations with enhanced antitumor performance remains a big challenge. Herein, we synthesize paclitaxel prodrugs with amphiphilic structures and robust assembling ability. Carboxylated paclitaxel prodrugs (PSCB) containing disulfide bonds prefer to form exquisite nanofibers, while phenylcarbinol end capped paclitaxel prodrugs (PSP) assemble into spherical nanoparticles. The transformation of morphology from nanofibers to nanorods can be realized via tuning the content of paclitaxel. Hydrophilic domains of PSCB nanofibers accelerate the cleavage of disulfide bond for rapid drug release in tumor cells, thus exhibiting the enhanced cytotoxicity and antitumor activity. This study provides a crucial insight into the functional design of hydrophobic drugs to improve chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rational design of efficient cytosolic protein delivery carriers holds enormous promise for biotherapeutics development. Several delivery systems have been developed during the past decades, while tailoring the balance between extracellular protein binding and intracellular cargo release is still challenging. In this study, we synthesized a series of oxygen-sensitive reactive polymers, rich in boron, by radical polymerization and post-modification for cytosolic protein delivery in vitro and in vivo. The introduction of boronate building blocks into the polymer scaffold significantly enhanced its protein binding affinity, and the polymer/protein complexes with high stability were obtained by tailoring the molecular ratios between the boronate ligands and the amine groups. The lead material screened from the polymer library exhibited efficient protein delivery efficacy that can release cargo proteins in cytosol in a reactive oxygen species responsive manner, which enables intracellular delivery of proteins with maintained bioactivity. In addition, the polymer-based nanoformulations efficiently delivered saporin, a toxin protein, into osteosarcoma cells and tumor tissues, and exhibited high therapeutic efficacy in an osteosarcoma mouse model. The synthesized polymer in this study can be developed as a promising nanocarrier for cytosolic delivery of protein therapeutics to treat a variety of diseases., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Atherosclerosis is a chronic disease initiated by lipid-mediated vascular inflammation. From the perspective of conventional treatment, it is difficult to achieve good therapeutic effects via regulation of a single lipid or anti-inflammatory effects. Herein, we designed an amphiphilic low molecular weight heparin-unsaturated fatty acid conjugate (LMWH-uFA) that acted as both an antiatherosclerotic agent and a nanocarrier with self-delivery properties. Structurally, LMWH-uFA self-assembled to form micelles with LMWH as the shell and uFA as the core, without any additives, which guaranteed their biosafety. Functionally, the hydrophilic segment, LMWH, prevented monocyte adhesion to inhibit early vascular inflammation, and the hydrophobic segment, uFA, could participate in the regulation of blood lipids. The anti-inflammatory drug rapamycin (RAP) was encapsulated in the micellar core, which improved its water solubility, and cooperated with LMWH to achieve targeted blockade of the vascular inflammation cascade at P-selectin. The three treatment modules, LMWH, uFA and RAP, were integrated into one system for different therapeutic targets in anticipation of better efficacy. In an atherosclerosis mouse model, RAP-loaded NPs significantly reduced the plaque area and showed satisfactory curative effects, which were related to the targeting of lipid regulation and inflammation. Thus, these modular micellar nanoparticles offer a promising approach for the clinical treatment of atherosclerosis., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023. Published by Elsevier B.V.)

The oral route is the most desirable drug administration path. The oral bioavailability is always compromised from the poor physicochemical and/or biopharmaceutical properties of the active pharmaceutical ingredients. Food protein nanoparticles show promise for oral drug delivery, with improved biosafety and cost-effectiveness compared to polymeric nanoparticles. More importantly, diverse food proteins provide "choice and variety" to meet the challenges faced by different drugs in oral delivery resulting from low solubility, poor permeability, and gastrointestinal stability. The abundance of hydroxyl, amino, and carboxyl groups in food proteins allows easy surface modification of the nanoparticles to impart unique functions. Albeit being in its infancy, food protein nanoparticles exhibit high capability to enhance oral bioavailability of a wide range of drugs from small molecules to biomacromolecules. Considering the rapid growth of the field, the achievements and mechanisms of food protein nanoparticles in enhancing oral bioavailability are reviewed. Factors affecting the performance of food protein nanoparticles are discussed with the purpose to inspire the development of food protein nanoparticle-based oral drug delivery systems., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nanocarrier-aided drug delivery techniques have improved the absorption and permeability of drugs in nose-to-brain delivery. However, the molecular properties of nanocarriers during the delivery process are of great interest; in particular, the characteristics when penetrating barriers in vivo are crucial for the screening and optimization of materials for nasal inhalation. In this study, we have focused on two types of delivery systems: mucoadhesive nanoparticles (MAPs) and mucopenetrating nanoparticles (MPPs); both have been widely used for mucosal delivery, although a method for selecting the more effective type of drug carriers for mucosal delivery has not been established. Molecular dynamics (MD) simulations were used to reveal the all-atom dynamic characteristics of the interaction between different delivery systems and the nasal mucus protein MUC5AC. Among the systems tested, hydroxypropyltrimethyl ammonium chloride chitosan (HTCC) had the strongest interaction with mucin, suggesting it had better mucoadhesive performance, and that it interacted with MUC5AC more strongly than unmodified chitosan. In contrast, the mucus-penetrating material polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA), had almost no interaction with MUC5AC. The results of the MD simulations were verified by in vitro experiments on nanoparticles (NPs) and mucin binding. The drug delivery performance of the four types of NPs, analyzed by in vitro and ex vivo mucosal penetration, were all generally consistent with the properties of the material predicted from the MD simulation. These clues to the molecular mechanism of MAPs and MPPs may provide useful insight into the screening and optimization of nanomaterials suitable for nasal inhalation., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nanomedicines are considered next generation therapeutics with advanced therapeutic properties and reduced side effects. Herein, we introduce tailored linear and star-like water-soluble nanosystems as stimuli-sensitive nanomedicines for the treatment of solid tumors or hematological malignancies. The polymer carrier and drug pharmacokinetics were independently evaluated to elucidate the relationship between the nanosystem structure and its distribution in the body. Positron emission tomography and optical imaging demonstrated enhanced tumor accumulation of the polymer carriers in 4T1-bearing mice with increased tumor-to-blood and tumor-to-muscle ratios. Additionally, there was a significant accumulation of doxorubicin bound to various polymer carriers in EL4 tumors, as well as excellent in vivo therapeutic activity in EL4 lymphoma and moderate efficacy in 4T1 breast carcinoma. The linear nanomedicine showed at least comparable pharmacologic properties to the star-like nanomedicines regarding doxorubicin transport. Therefore, if multiple parameters are considered such as its optimized structure and simple and reproducible synthesis, this polymer carrier system is the most promising for further preclinical and clinical investigations., Competing Interests: Declaration of Competing Interest Weibo Cai is a scientific advisor, stockholder, and grantee of Focus-X Therapeutics, Inc. All other authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The drug efflux by P-glycoprotein (P-gp) is the primary contributor of multidrug resistance (MDR), which eventually generates insufficient nuclear drug accumulation and chemotherapy failure. In this paper, reversible covalent nanoassemblies on the basis of catechol-functionalized methoxy poly (ethylene glycol) (mPEG-dop) and phenylboronic acid-modified cholesterol (Chol-PBA) are successfully synthesized for delivery of both doxorubicin (DOX, anti-cancer drug) and tariquidar (TQR, P-glycoprotein inhibitor), which shows efficient nuclear DOX accumulation for overcoming tumor MDR. Through naturally forming phenylboronate linkage in physiological circumstances, Chol-PBA is able to bond with mPEG-dop. The resulting conjugates (PC) could self-assemble into reversible covalent nanoassemblies by dialysis method, and transmission electron microscopy analysis reveals the PC distributes in nano-scaled spherical particles before and after drug encapsulation. Under the assistance of Chol, PC can enter into lysosome of tumor cells via low-density lipoprotein (LDL) receptor-mediated endocytosis. Then the loaded TQR and DOX are released in acidic lysosomal compartments, which inhibit P-gp mediated efflux and elevate nuclear accumulation of DOX, respectively. At last, this drug loaded PC nanoassemblies show significant tumor suppression efficacy in multidrug-resistant tumor models, which suggests great potential for addressing MDR in cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sepsis, a consequence of an imbalanced immune response to infection, is currently one of the leading causes of death globally. Despite advances in the discoveries of potential targets and nanotechnology, sepsis still lacks effective drug delivery systems for optimal treatment. Stimuli-responsive and biomimetic nano delivery systems, specifically, are emerging as advanced bio-inspired nanocarriers for enhancing the treatment of sepsis. Herein, we present a critical review of different stimuli-responsive systems, including pH-; enzyme-; ROS- and toxin-responsive nanocarriers, reported in the delivery of therapeutics for sepsis. Biomimetic nanocarriers, utilizing natural pathways in the inflammatory cascade to optimize sepsis therapy, are also reviewed, in addition to smart, multifunctional vehicles. The review highlights the nanomaterials designed for constructing these systems; their physicochemical properties; the mechanisms of drug release; and their potential for enhancing the therapeutic efficacy of their cargo. Current challenges are identified and future avenues for research into the optimization of bio-inspired nano delivery systems for sepsis are also proposed. This review confirms the potential of stimuli-responsive and biomimetic nanocarriers for enhanced therapy against sepsis and related complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Diabetes mellitus is a long-term chronic disease characterized by abnormal high level blood glucose (BG). An artificial closed-loop system that mimics pancreatic β-cells and releases insulin on demand has potential to improve the therapeutic efficiency of diabetes. Herein, a lectin Concanavalin A modified oxidized starch nanogel was designed to regulate glucose dynamically according to different glucose concentrations. The nanogels were formed by double cross-linking the Concanavalin A and glucose units on oxidized starch via specific binding and amide bonds to achieve the high drug loading and glucose responsiveness. The results showed that oxidized starch nanogels prolonged the half-life of antidiabetic peptide drug exenatide and released it in response to high BG concentrations. It could absorb BG at a high level and maintain glucose homeostasis. Besides, the oxidized starch nanogels performed well in recovering regular BG level from hyperglycemia state and maintaining in euglycemia state that fitted in a biological rhythm. In addition, the nanogels showed high biocompatibility in vivo and could improve plasma half-life and therapeutic efficacy of exenatide. Overall, the nanogels protected peptide drugs from degradation in plasma as a glucose-responsive platform showing a high potential for peptide drugs delivery and antidiabetic therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This research demonstrates the development, application, and mechanistic value of a multi-detector asymmetric flow field-flow fractionation (AF4) approach to acquire size-resolved drug loading and release profiles from polymeric nanoparticles (NPs). AF4 was hyphenated with multiple online detectors, including dynamic and multi-angle light scattering for NP size and shape factor analysis, fluorescence for drug detection, and total organic carbon (TOC) to quantify the NPs and dissolved polymer in nanoformulations. The method was demonstrated on poly(lactic-co-glycolic acid) (PLGA) NPs loaded with coumarin 6 (C6) as a lipophilic drug surrogate. The bulk C6 release profile using AF4 was validated against conventional analysis of drug extracted from the NPs and complemented with high performance liquid chromatography - quadrupole time-of-flight (HPLC-QTOF) mass spectrometry analysis of oligomeric PLGA species. Interpretation of the bulk drug release profile was ambiguous, with several release models yielding reasonable fits. In contrast, the size-resolved release profiles from AF4 provided critical information to confidently establish the release mechanism. Specifically, the C6-loaded NPs exhibited size-independent release rate constants and no significant NP size or shape transformations, suggesting surface desorption rather than diffusion through the PLGA matrix or erosion. This conclusion was supported through comparative experimental evaluation of PLGA NPs carrying a fully entrapped drug, enrofloxacin, which showed size-dependent diffusive release, along with density functional theory (DFT) calculations indicating a higher adsorption affinity of C6 onto PLGA. In summary, the development of the size-resolved AF4 method and data analysis framework fulfills salient analytical gaps to determine drug localization and release mechanisms from nanomedicines., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)