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Background: Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle., Results: Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8 + T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier., Conclusions: Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses., (© 2024. The Author(s).)

Introduction: Photoaging-induced skin damage leads to appearance issues and dermatoma. Selenium nanoparticles (SeNPs) possess high antioxidant properties but are prone to inactivation. In this study, human serum albumin/SeNPs (HSA-SeNPs) were synthesized for enhanced stability., Methods: HSA-SeNPs were prepared by self-assembling denatured human serum albumin and inorganic selenite. The cytotoxicity of HSA-SeNPs was assessed using the MTT method. Cell survival and proliferation rates were tested to observe the protective effect of HSA-SeNPs on human skin keratinocytes against photoaging. Simultaneously, ICR mice were used for animal experiments. H&E and Masson trichromatic staining were employed to observe morphological changes in skin structure and collagen fiber disorders after UVB irradiation. Quantitative RT-PCR was utilized to measure changes in mRNA expression levels of factors related to collagen metabolism, inflammation, oxidative stress regulation, and senescence markers., Results: The HSA-SeNPs group exhibited significantly higher survival and proliferation rates of UVB-irradiated keratinocytes than the control group. Following UVB irradiation, the back skin of ICR mice displayed severe sunburn with disrupted collagen fibers. However, HSA-SeNPs demonstrated superior efficacy in alleviating these symptoms compared to SeNPs alone. In a UVB-irradiated mice model, mRNA expression of collagen type I and III was dysregulated while MMP1, inflammatory factors, and p21 mRNA expression were upregulated; concurrently Nrf2 and Gpx1 mRNA expression were downregulated. In contrast, HSA-SeNPs maintained the mRNA expression of those factors to be stable In addition, the level of SOD decreased, and MDA elevated significantly in the skin after UVB irradiation, but no significant differences in SOD and MDA levels between the HSA-SeNPs group with UVB irradiation and the UVB-free untreated group., Discussion: HSA-SeNPs have more anti-photoaging effects on the skin than SeNPs, including the protective effects on skin cell proliferation, cell survival, and structure under photoaging conditions. HSA-SeNPs can be used to protect skin from photoaging and repair skin injury caused by UVB exposure., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yao et al.)

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles., (© 2024. The Author(s).)

With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H 2 O 2 , and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.

The combination of small-interfering RNA (siRNA)-mediated gene silencing and chemotherapeutic agents for lung cancer treatment has attracted widespread attention in terms of a greater therapeutic effect, minimization of systemic toxicity, and inhibition of multiple drug resistance (MDR). In this work, three amphiphiles, CBN1 - CBN3 , were first designed and synthesized as a camptothecin (CPT) conjugate and gene condensation agents by the combination of CPT prodrugs and di(triazole-[12]aneN 3 ) through the ROS-responsive phenylborate ester and different lengths of alkyl chains (with 6, 9, 12 carbon chains for CBN1 - CBN3 , respectively). CBN1 - CBN3 were able to be self-assembled into liposomes with an average diameter in the range of 320-240 nm, showing the ability to effectively condense siRNA. Among them, CBN2 , with a nine-carbon alkyl chain, displayed the best anticancer efficiency in A549 cells. In order to give nanomedicines a stealth property and PEGylation/dePEGylation transition, a GSH-responsive PEGylated TPE derivative containing a disulfide linkage ( TSP ) was further designed and prepared. A combination of CBN2 /siRNA complexes and DOPE with TSP resulted in GSH/ROS dual-responsive lipid-polymer hybrid nanoparticles ( CBN2-DP /siRNA NPs). In present GSH and H 2 O 2 , CBN2-DP /siRNA NPs were decomposed, resulting in the controlled release of CPT drug and siRNA. In vitro , CBN2-DP /siPHB1 NPs showed the best anticancer activity for suppression of about 75% of A549 cell proliferation in a serum medium. The stability of CBN2-DP /siRNA NPs was significantly prolonged in blood circulation, and they showed effective accumulation in the A549 tumor site through an enhanced permeability and retention (EPR) effect. In vivo , CBN2-DP /siPHB1 NPs demonstrated enhanced synergistic cancer therapy efficacy and tumor inhibition as high as 71.2%. This work provided a strategy for preparing lipid-polymer hybrid NPs with GSH/ROS dual-responsive properties and an intriguing method for lung cancer therapy.

Ferroptosis, a unique iron-dependent mode of cell death characterized by lipid peroxide accumulation, holds significant potential for the treatment of glioblastoma (GBM). However, the effectiveness of ferroptosis is hindered by the limited intracellular ferrous ions (Fe 2+ ) and hydrogen peroxide (H 2 O 2 ). In this study, a novel near-infrared (NIR)-light-responsive nanoplatform (ApoE-UMSNs-GOx/SRF) based on upconversion nanoparticles (UCNPs) was developed. A layer of mesoporous silica and a lipid bilayer were coated on UCNPs sequentially and loaded with glucose oxidase (GOx) and sorafenib, respectively. Further attachment of the ApoE peptide endowed the nanoplatform with BBB penetration and GBM targeting capabilities. Our results revealed that ApoE-UMSNs-GOx/SRF could efficiently accumulated in the orthotopic GBM and induce amplified ferroptosis when combining with NIR irradiation. The UCNPs mediated the photoreduction of Fe 3+ to Fe 2+ by converting NIR to UV light, and excess H 2 O 2 was produced by the reaction of glucose with the loaded GOx. These processes greatly promoted the production of ROS, which together with inhibition of system Xc - by the loaded sorafenib, leading to enhanced accumulation of lipid peroxides and significantly improved the antiglioma effect both in vitro and in vivo. Our strategy has the potential to enhance the effectiveness of ferroptosis as a therapeutic approach for GBM., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immune checkpoint blockade (ICB) therapy still suffers from insufficient immune response and adverse effect of ICB antibodies. Chemodynamic therapy (CDT) has been demonstrated to be an effective way to synergize with ICB therapy. However, a low generation rate of reactive oxygen species and poor tumor penetration of CDT platforms still decline the immune effects. Herein, a charge-reversal nanohybrid Met@BF containing both Fe 3 O 4 and BaTiO 3 nanoparticles in the core and Metformin (Met) on the surface was fabricated for tumor microenvironment (TME)- and ultrasound (US)-activated piezocatalysis-chemodynamic immunotherapy of cancer. Interestingly, Met@BF had a negative charge in blood circulation, which was rapidly changed into positive when exposed to acidic TME attributed to quaternization of tertiary amine in Met, facilitating deep tumor penetration. Subsequently, with US irradiation, Met@BF produced H 2 O 2 based on piezocatalysis of BaTiO 3 , which greatly enhanced the Fenton reaction of Fe 3 O 4 , thus boosting robust antitumor immune response. Furthermore, PD-L1 expression was inhibited by the local released Met to further augment the antitumor immune effect, achieving effective inhibitions for both primary and metastatic tumors. Such a combination of piezocatalysis-enhanced chemodynamic therapy and Met-mediated deep tumor penetration and downregulation of PD-L1 provides a promising strategy to augment cancer immunotherapy.

Pickering emulsions have attracted considerable attention owing to the stability and functionality. In this study, zein/hyaluronic acid (ZH) nanoparticles were prepared and applied for stabilizing astaxanthin encapsulated Pickering emulsions. By non-covalent interaction between Zein and hyaluronic acid (HA), the conformation of zein changed and therefore improved the wettability of ZH nanoparticles. Unlike the spherical zein nanoparticles, ZH nanoparticles possessed a cross-linked structure with rough surface. Confocal laser scanning microscopy indicated that the nanoparticles accumulated at the oil-water interface. The Pickering emulsion stabilized by ZH nanoparticles exhibited high viscoelasticity and a solid-like behavior, as well as excellent stability during the storage. In vitro digestion results revealed that the presence of HA coating prevented the emulsion from pepsin hydrolysis and achieved efficient delivery of astaxanthin. This work confirmed that Pickering emulsion stabilized by ZH nanoparticles could be used as an effective deliver system for bioactive substances., 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 Elsevier B.V. All rights reserved.)

The clinical application of photodynamic therapy (PDT) is limited by the lack of tumor selectivity of photosensitizer (PS) and the hypoxic tumor microenvironment (TME). To address these limitations of PDT, we developed a hybrid engineered biointerface nanoplatform that integrated anti-epidermal growth factor receptor (EGFR)-aptamer (EApt)-modified liposomes with tumor cell membranes (TMs) to create M/L-EApt. M/L-EApt exhibited enhanced stability and significant dual-targeting ability, enabling selectively accumulate in hypoxic tumor regions after systemic infusion. PHI@M/L-EApt, formed by M/L-EApt loaded with an oxygen carrier perfluorotributylamine (PFTBA) and IR780 (a PS), effectively promoted the therapeutic performance of PDT by reversing the hypoxic TME and increasing the accumulation of IR780 at the tumor sites, resulting in a robust anti-tumor efficacy. In vivo results showed that PHI@M/L-EApt treatment effectively suppressed the growth of triple-negative breast tumors in mice. Our findings demonstrated the synergistic effect of oxygen supply and PDT on tumor treatment using PHI@M/L-EApt. This study presented a biomimetic interface engineering strategy and dual-targeted hybrid nanoplatform for relieving hypoxic TME and potentially facilitating the clinical application of PDT., 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 Elsevier Inc. All rights reserved.)

Liver fibrosis is featured by activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM). The Golgi apparatus in HSCs plays a vital role in synthesis and secretion of ECM proteins, while its targeted disruption in activated HSCs could be considered as a promising approach for liver fibrosis treatment. Here, we developed a multitask nanoparticle CREKA-CS-RA (CCR) to specifically target the Golgi apparatus of activated HSCs, based on CREKA (a specific ligand of fibronectin) and chondroitin sulfate (CS, a major ligand of CD44), in which retinoic acid (a Golgi apparatus-disturbing agent) chemically conjugated and vismodegib (a hedgehog inhibitor) encapsulated. Our results showed that CCR nanoparticles specifically targeted activated HSCs and preferentially accumulated in the Golgi apparatus. Systemic administration of CCR nanoparticles exhibited significantly accumulation in CCl 4 -induced fibrotic liver, which was attributed to specific recognition with fibronectin and CD44 on activated HSCs. CCR nanoparticles loaded with vismodegib not only disrupted Golgi apparatus structure and function but also inhibited the hedgehog signaling pathway, thus markedly suppressing HSC activation and ECM secretion in vitro and in vivo. Moreover, vismodegib-loaded CCR nanoparticles effectively inhibited the fibrogenic phenotype in CCl 4 -induced liver fibrosis mice without causing obvious toxicity. Collectively, these findings indicate that this multifunctional nanoparticle system can effectively deliver therapeutic agents to the Golgi apparatus of activated HSCs, thus has potential treatment of liver fibrosis with minimal side 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 © 2023. Published by Elsevier Ltd.)

In situ mitochondrial oxidative stress amplification is an effective strategy to improve efficacy of cancer treatment. In this work, a tumor and mitochondria dual-targeted multifunctional nanoplatform CMS@AIPH@PDA@COTPP@FA (CAPCTF) was prepared, in which a thermally decomposable radical initiator AIPH was loaded inside the mesoporores of Cu x Mo y S z (CMS) nanoparticles with polydopamine (PDA) covered films that were further covalently functionalized by a mitochondria-targeted CO donor (COTPP) and a directing group of folic acid (FA). The prepared CAPCTF nanoplatform selectively accumulated in cancer cells and further targeted the mitochondrial organelle where carbon monoxide (CO) and O 2 -independent free radicals (•OH/•R) were in situ generated upon 1064 nm laser irradiation. Furthermore, the CMS nanocarrier was capable of depleting the GSH overexpressed in the tumor microenvironment (TME), thus preventing free radical scavenging. As a result, the CAPCTF nanoplatform exhibited outstanding in vitro and in vivo antitumor efficacy under hypoxic conditions. This provides an innovative strategy that combines O 2 -independent free radicals (•OH/•R) generation, CO delivery and GSH consumption to amplify intracellular oxidative stresses and induce mitochondrial dysfunction, thus leading to cancer cells eradication, which may have significant implications for personalized hypoxic tumor treatment., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A novel dual-responsive nanoparticle (NP) system was aimed to be developed for the co-delivery of camptothecin (CPT) and plasmid encoding TNF-related apoptosis-inducing ligand (pTRAIL) DNA in cancer therapy. The combination of the prodrug CPT and the nucleic acid condensing di-(triazole-[12]aneN3) unit with 4-nitrobenzyl ester through alkyl chains resulted in three nitroreductase (NTR) responsive amphiphiles, CNN1-CNN3 (with 5, 8, and 11 carbon chains, respectively). Among them, CNN2 was the most effective in inhibiting the proliferation of HeLa cells in the presence of fusogenic lipid DOPE. The NPs composed of CNN2, pDNA, and DOPE were further co-assembled with ROS-responsive thioketal-linked amphiphilic polymer (TTP) to afford the core-shell NPs (CNN2-DT/pDNA) with an average size of 118 nm, which exhibited high drug-loading capacity, excellent serum tolerance, and good biocompatibility. In the presence of ROS, NTR, and NADH, the core-shell NPs were decomposed, leading to the efficient release of 80% CPT and abundant pDNA. The self-assembly and delivery process of CNN2-DT NPs and DNA were clearly observed through the AIE fluorescent imaging. In vitro and in vivo results demonstrated that the CNN2-DT/pTRAIL NPs synergistically promoted 68% apoptosis of tumor cells and inhibited tumor growth with negligible toxic side effects. This study showed that the combination of prodrug and nucleic acid through dual-responsive core-shell NPs provide a spatially and temporally-controlled strategy for cancer therapy.

Piezoelectric nanomaterials have become increasingly popular in the field of biomedical applications due to their high biocompatibility and ultrasound-mediated piezocatalytic properties. In addition, the ability of these nanomaterials to disaggregate amyloid proteins, which are responsible for a range of diseases resulting from the accumulation of these proteins in body tissues and organs, has recently gained considerable attention. However, the use of nanoparticles in biomedicine poses significant challenges, including targeting and uncontrolled aggregation. To address these limitations, our study proposes to load these functional nanomaterials on a multifunctional mobile microrobot (PiezoBOT). This microrobot is designed by coating magnetic and piezoelectric barium titanate nanoparticles on helical biotemplates, allowing for the combination of magnetic navigation and ultrasound-mediated piezoelectric effects to target amyloid disaggregation. Our findings demonstrate that acoustically actuated PiezoBOTs can effectively reduce the size of aggregated amyloid proteins by over 80% in less than 10 minutes by shortening and dissociating constituent amyloid fibrils. Moreover, the PiezoBOTs can be easily magnetically manipulated to actuate the piezocatalytic nanoparticles to specific amyloidosis-affected tissues or organs, minimizing side effects. These biocompatible PiezoBOTs offer a promising non-invasive therapeutic approach for amyloidosis diseases by targeting and breaking down protein aggregates at specific organ or tissue sites.

The strategies that allow one single device to possess multiple controlled micro-/nano-manipulation functions are demanded by various fields. In this work, we have developed a probe-type ultrasonic sweeper with rich micro-/nano-manipulation functions, including concentration, decorating, transmedium extraction, and removal of micro-/nanoscale materials at the interface between a suspension film and a non-vibration substrate. The functions are implemented with a micro-manipulation probe (MMP) in contact with the substrate, which vibrates approximately linearly and perpendicularly to the substrate. Silver nanowires on the substrate can be sucked onto the vibrating MMP's tip and accumulate to form a microsheet. By moving the MMP horizontally, nanowires on its motional path can be sucked onto the MMP's tip, and controlled cleaning can be realized. If nanoparticles are mixed into the AgNW suspension uniformly, AgNWs in the accumulated microsheet can be decorated with the nanoparticles. More importantly, the accumulated nanomaterials on the MMP's tip can be transported freely in the suspension film and even extracted into air from the liquid film. To the best of our knowledge, the ultrasonic sweeper in this work possesses the richest micro-/nano-manipulation functions than any other existing acoustic manipulators. The finite element analyses indicate that the multiple manipulation functions achieved are caused by the acoustic radiation force generated by the ultrasonic field in the suspension film., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Most injectable preparations for the articular cavity are solution-type preparations that are frequently administered because of rapid elimination. In this study, triptolide (TPL), an effective ingredient in the treatment of rheumatoid arthritis (RA), was prepared in the form of a nanoparticle thermosensitive gel (TPL-NS-Gel). The particle size distribution and gel structure were investigated by TEM, laser particle size analysis and laser capture microdissection. The effect of the nanoparticle carrier material PLGA on the phase transition temperature was investigated by 1 H variable temperature NMR and DSC. The tissue distribution, pharmacokinetic behavior, four inflammatory factors and therapeutic effect were determined in a rat RA model. The results suggested that PLGA increased the gel phase transition temperature. The drug concentration of the TPL-NS-Gel group in joint tissues was higher than that in other tissues at different time points, and the retention time was longer than that of the TPL-NS group. After 24 days of administration, TPL-NS-Gel significantly improved the joint swelling and stiffness of the rat models, and the improvement degree was better than that of the TPL-NS group. TPL-NS-Gel significantly decreased the levels of hs-CRP, IL-1, IL-6 and TNF-α in serum and joint fluid. There was a significant difference between the TPL-NS-Gel and TPL-NS groups on Day 24 ( p < 0.05). Pathological section results showed that inflammatory cell infiltration was lower in the TPL-NS-Gel group, and no other obvious histological changes were observed. Upon articular injection, the TPL-NS-Gel prolonged drug release, reduced the drug concentration outside the articular tissue and improved the therapeutic effect in a rat RA model. The TPL-NS-Gel can be used as a new type of sustained-release preparation for articular injection.

Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non-specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)-activated PD-L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD-L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O 2 based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD-L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2-activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD-L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor., (© 2023 Wiley-VCH GmbH.)

Conventional NO gas generation based on l-arginine (l-Arg) is usually dependent on H 2 O 2 and O 2 , both of which are very limited within the tumor microenvironment, thus greatly limiting l-Arg's therapeutic effect. Herein, a novel nanoplatform for efficiently triggering NO production based on ultrasound-induced piezocatalysis was developed, which was fabricated by coating amphiphilic poly-l-arginine (DSPE-PEG 2000 -Arg, DPA) on the piezoelectric material of barium titanate (BTO). The resulting BTO@DPA nanoparticles can efficiently generate H 2 O 2 , 1 O 2 , and O 2 via ultrasound-induced piezocatalysis based on BTO and oxidize the surface arginine to produce NO, which can even further interact with the reactive oxygen species (ROS) to produce more reactive peroxynitrite, thus inducing serious tumor cell apoptosis both in hypoxia and normoxia. After intravenous injection, BTO@DPA accumulated well at the tumor tissue at 4 h postinjection; later, ultrasound irradiation on the tumor not only achieved the best tumor inhibition rate of ∼70% but also completely inhibited tumor metastasis to the lungs via the alleviation of tumor hypoxia. Such a strategy was not dependent on the tumor microenvironment and can be well controlled by ultrasound irradiation, providing a simple and efficient therapy paradigm for hypoxic tumor.

Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10-20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis, which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes. After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Nitric oxide (NO) is drawing widespread attention in treating pancreatic ductal adenocarcinoma (PDAC) as a safe and therapeutically efficient technique through modulating the dense fibrotic stroma in the tumor microenvironment to enhance drug penetration. Considerable NO nanogenerators and NO releasing molecules have been developed to shield the systemic toxicity caused by free diffusion of NO gas. However, on-demand controlled release of NO and chemotherapy drugs at tumor sites remains a problem limited by the complex and dynamic tumor microenvironment. Herein, we present an ultrasound-responsive nanoprodrug of CPT-t-R-PEG 2000 @BaTiO 3 (CRB) which encapsulates piezoelectric nanomaterials barium titanate nanoparticle (BaTiO 3 ) with amphiphilic prodrug molecules that consisted of thioketal bond (t) linked chemotherapy drug camptothecin (CPT) and NO-donor l-arginine (R). Based on ultrasound-triggered piezocatalysis, BaTiO 3 can continuously generate ROS in the hypoxic tumor environment, which induces a cascade of reaction processes to break the thioketal bond to release CPT and oxidize R to release NO, simultaneously delivering CPT and NO to the tumor site. It is revealed that CRB shows a uniform size distribution, prolonged blood circulation time, and excellent tumor targeting ability. Moreover, controlled release of CPT and NO were observed both in vitro and in vivo under the stimulation of ultrasound, which is beneficial to the depletion of dense stroma and subsequently enhanced delivery and efficacy of CPT. Taken together, CRB significantly increased the antitumor efficacy against highly malignant Panc02 tumors in mice through inhibiting chemoresistance, representing a feasible approach for targeted therapies against Panc02 and other PDAC.

Arsenic trioxide (As 2 O 3 , ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

Tumor phototheranostics holds a great promise on account of its high spatiotemporal resolution, tumor-specificity, and noninvasiveness. However, physical limitation of light penetration and "always on" properties of conventional photothermal-conversion agents usually cause difficulty in accurate diagnosis and completely elimination of tumor. Meanwhile, nanozymes mediated Fenton reactions can well utilize the tumor microenvironment (TME) to generate hydroxyl radicals for chemodynamic therapy (CDT), but limited by the concentration of H 2 O 2 in TME and the delivery efficiency of nanozymes. To overcome these problems, a dual-targeting nanozyme (FTRNPs) is developed for tumor-specific in situ theranostics, based upon the assembling of ultrasmall Fe 3 O 4 nanoparticles, 3,3',5,5'-tetrameth-ylbenzidine (TMB) and the RGD peptide. The FTRNPs after H 2 O 2 treatment exhibits superior photothermal stability and high photothermal conversion efficiency (η = 50.9%). FTRNPs shows extraordinary accumulation and retention in the tumor site by biological/physical dual-targeting, which is 3.54-fold higher than that without active targeting. Cascade-dual-response to TME for nanozymes mediated Fenton reactions and TMB oxidation further improves the accuracy of both photoacoustic imaging and photothermal therapy (PTT). The tumor inhibition rate of photo-chemodynamic therapy is ~ 97.76%, which is ~ 4-fold higher than that of PTT or CDT only. Thus, the combination of CDT and PTT to construct "turn on" nanoplatform is of great significance to overcome their respective limitations. Considering its optimized "all-in-one" performance, this new nanoplatform is expected to provide an advanced theranostic strategy for the future treatment of cancers., (© 2022. The Author(s).)

Owing to the complementary high spatial resolution and signal-to-noise ratio, the dual-modality imaging technique of photoacoustic imaging (PAI)/the second near-infrared window fluorescence imaging (NIR-II FI) holds great promise for the detection of tumor tissues and sentinel lymph nodes (SLNs). Herein, by developing two aggregation-induced emission luminogens (AIEgens) (C-NTBD and O-NTBD) with benzodithiadiazole as the electron acceptor, PAI/NIR-II FI was applied to the diagnosis and treatment of neuroendocrine neoplasms (NENs) and their SLNs for the first time. Both AIEgens exhibited good PAI properties as well as intense NIR-II fluorescence emission. Among them, C-NTBD nanoparticles (NPs) have better PAI and NIR-II FI performance with maximum absorption at 732 nm and emission peak at 1042 nm. In NENs-bearing nude mice model, after successful preoperative localization of NENs by PAI, NIR-II FI was then used to detect SLNs. Under the NIR-II FI guidance of C-NTBD NPs, an SLN with a diameter of 1 mm located in the chest wall and far away from the primary tumor site was even detected and precisely removed. This dual-modality imaging technology could improve the detection of NENs and the accuracy of intraoperative SLNs dissection, improve patient prognosis, and provide a new strategy for the precise treatment of NENs., 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 © 2022 Elsevier Ltd. All rights reserved.)

Nanocrystalline cellulose (NCC) have gained great attention owing to their extraordinary properties such as biocompatibility, biodegradability, high crystallinity index (>70%), large surface area (~150 m 2 /g), high aspect ratio (~70), and high tensile strength (7500 MPa). Bast fibers, with compelling features of easy availability, high fiber length, and high cellulose content, are considered to be competitive raw materials to prepare high quality NCC. Generally, NCC can be obtained by mechanical, chemical, biological or combining methods with the removal of non-cellulosic components from bast fibers. This work summarizes the comprehensive research advancement of NCC extracted from bast fibers. Comparison analysis of geometrical dimensions and microstructure morphologies of NCC are conducted to evaluate the strengths and weaknesses of each preparation method. The characterization of NCC and the application of NCC in many emerging fields are systematically introduced. A detailed discussion of current challenges and future outlook are provided to inspire the relevant researchers., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Photoactivated chemotherapy has attracted widespread attention due to its ability to circumvent the shortcomings of hypoxia in tumor tissues compared with traditional photodynamic therapy. In this work, novel multifunctional nanoplatform (1), Ru-inhibitor@TPPMnCO@N-GQDs, was designed and prepared, which was capable of mitochondria-targeted co-delivery of the cysteine protease inhibitor and carbon monoxide (CO) stimulated with an 808 nm near infrared (NIR) laser. Nanoplatform (1) was prepared by covalent attachment of a mitochondria-targeted CO donor (TPPMnCO) and a Ru(II)-caged cysteine protease inhibitor (Ru-inhibitor) on the surface of fluorescent N-doped graphene quantum dots (N-GQDs). Nanoplatform (1) preferentially accumulated in the mitochondria of cancer cells and instantly delivered CO and the cysteine protease inhibitor upon 808 nm NIR light irradiation, thus damaging mitochondria and leading to significant in vitro and in vivo anticancer efficacy. In addition, nanoplatform (1) has good biocompatibility and did not exert any toxic side effects on mice during the period of treatment. The targeted subcellular mitochondrial co-delivery of CO and the cysteine protease inhibitor may provide new insights into CO and enzyme inhibitor combined therapies for cancer treatment.

In this study, the fucoxanthin (FUC)-loaded gliadin nanoparticles (Gli NPs) stabilized by chondroitin sulfate (ChS) were fabricated. Results showed that the particle size and turbidity of Gli-ChS NPs were highly pH-dependent. Hydrogen bond, electrostatic interaction and hydrophobic interaction were involved in the formation of Gli-ChS NPs. The surface hydrophobicity of Gli NPs decreased remarkably after coating with ChS. FUC-Gli-ChS NPs increased the stability of FUC against heating and ultraviolet (UV) irradiation. Adding ChS to FUC-Gli NPs enhanced their stabilities to ionic strength and thermal treatment, especially in an acidic environment. Furthermore, FUC-loaded Gli-ChS NPs inhibited the FUC release in simulated gastric fluid (SGF), while enhanced the release of FUC in simulated intestinal fluid (SIF) and simulated colonic fluid (SCF). In summary, this work has important practical significance for the development of Gli NPs as nano-delivery systems for FUC or other hydrophobic compounds., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bioinspired polydopamine (PDA) nanoparticles were synthesized and explored as functional compatibilizers in polyvinyl alcohol/starch (PVA/ST) matrix to develop high-performance multifunctional packaging film. The effect of the addition of PDA on the microstructural, mechanical, thermal, water vapor barrier, ultraviolet (UV)/high-energy blue light (HEBL) blocking, thermal insulating and antioxidant properties of PVA/ST composite films was fully investigated. Results demonstrated that the added PDA nanoparticles were evenly dispersed in the PVA/ST matrix, providing compact and dense nanocomposite films due to their compatibilization effect. Compared with virgin PVA/ST film, the resulting PVA/ST/PDA nanocomposite films exhibited greatly improved tensile strength, toughness, thermal stability, and water vapor barrier ability. Furthermore, the presence of PDA endowed PVA/ST composite film with excellent UV/HEBL blocking, thermal insulating as well as antioxidant functions. Thus, such high-performance multifunctional nanocomposite films hold the potential of protecting food quality against photothermal oxidative deterioration and extend food shelf life., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives, in situ gelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackable in vivo . In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic., (© 2022 IOP Publishing Ltd.)

As a novel type of antibiotic alternative, peptide-based antibacterial drug shows potential application prospects attributable to their unique mechanism for lysing the membrane of pathogenic bacteria. However, peptide-based antibacterial drugs suffer from a series of problems, most notably their immature stability, which seriously hinders their application. In this study, self-assembling chimeric peptide nanoparticles (which offer excellent stability in the presence of proteases and salts) are constructed and applied to the treatment of bacterial infections. In vitro studies are used to demonstrate that peptide nanoparticles NPs1 and NPs2 offer broad-spectrum antibacterial activity and desirable biocompatibility, and they retain their antibacterial ability in physiological salt environments. Peptide nanoparticles NPs1 and NPs2 can resist degradation under high concentrations of proteases. In vivo studies illustrate that the toxicity caused by peptide nanoparticles NPs1 and NPs2 is negligible, and these nanoparticles can alleviate systemic bacterial infections in mice and piglets. The membrane permeation mechanism and interference with the cell cycle differ from that of antibiotics and mean that the nanoparticles are at a lower risk of inducing drug resistance. Collectively, these advances may accelerate the development of peptide-based antibacterial nanomaterials and can be applied to the construction of supramolecular nanomaterials., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

This work explored biodegradable polyvinyl alcohol/starch (PVA/ST) film compatibilized by rod-like ZnO nanofillers as multifunctional food packaging materials. The influence of rod-like ZnO nanofillers on the microstructural, UV-shielding, antibacterial, mechanical, thermal, together with water barrier performances of PVA/ST composite films was fully studied. Results revealed that rod-like ZnO nanofillers could be uniformly distributed into the PVA/ST matrix, playing the role of compatibilizers to provide compact and dense nanocomposite films. The resulting nanocomposite films presented greatly improved mechanical and water vapor barrier properties as compared to virgin PVA/ST film. Moreover, the well distributed ZnO endowed PVA/ST film with excellent antimicrobial activity against both E. coli and S. aureus, together with outstanding UV-shielding capability meanwhile retaining highly optical transparency (approximately 90%). The developed PVA/ST/ZnO films were tested for packaging fresh-cut carrot slices to prevent microbial infection and prolong their shelf life. These results indicated that the developed highly transparent and multifunctional PVA/ST/ZnO nanocomposite films possess broad application prospects in active food packaging field., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As a traditional treatment for papillary thyroid cancer (PTC), surgical resection of diseased tissues often brings lots of inconveniences to patients, and the tumor recurrence and metastasis are difficult to avoid. Herein, we developed a gene and photothermal combined therapy nanosystem based on a polypyrrole (Ppy)-poly(ethylene imine)-siILK nanocomplex (PPR ILK ) to achieve minimally invasive ablation and lymphatic metastasis inhibition in PTC simultaneously. In this system, gelatin-stabilized Ppy mainly acted as a photothermal- and photoacoustic (PA)-responsive nanomaterial and contributed to its well-behaved photosensitivity in the near-infrared region. Moreover, gelatin-stabilized Ppy possessed a charge reversal function, facilitating the tight conjunction of siILK gene at physiological pH (7.35-7.45) and its automatic release into acidic lysosomes (pH 4.0-5.5); the proton sponge effect generated during this process further facilitated the escape of siILK from lysosomes to the cytoplasm and played its role in inhibiting PTC proliferation and lymphatic metastasis. With the guidance of fluorescence and PA bimodal imaging, gene delivery and Ppy location in tumor regions could be clearly observed. As a result, tumors were completely eradicated by photothermal therapy, and the recurrences and metastases were obviously restrained by siILK.

Introduction: Triple-negative breast cancer (TNBC) has the high degree of malignancy and aggressiveness. There is no targeted therapy drug. Many studies have shown that RBC membrane-coated nanoparticles achieve biological camouflage. In addition, the RGD module in the iRGD mediates the penetration of the vector across the tumor blood vessels to the tumor tissue space. Therefore, we developed iRGD-RM-(DOX/MSNs) by preparing MSNs loaded with doxorubicin as the core, and coating the surface of the MSNs with iRGD-modified RBC membranes., Methods: iRGD-RM-(DOX/MSNs) were fabricated using physical extrusion. In addition, their physical and chemical characterization, hemolytic properties, in vivo acute toxicity and inflammatory response, in vitro and in vivo safety, and qualitative and quantitative cellular uptake by RAW 264.7 cells and MDA-MB-231 cells were evaluated and compared. Furthermore, we examined the antitumor efficacy of iRGD-RM-(DOX/MSN) nanoparticles in vitro and in vivo., Results: iRGD-RM-(DOX/MSNs) have reasonable physical and chemical properties. iRGD-RM-(DOX/MSNs) escaped the phagocytosis of immune cells and achieved efficient targeting of nanoparticles at the tumor site. The nanoparticles showed excellent antitumor effects in vivo and in vitro., Conclusion: In this study, we successfully developed biomimetic iRGD-RM-(DOX/MSNs) that could effectively target tumors and provide a promising strategy for the effective treatment of TNBC., Competing Interests: The authors declare no conflicts of interest., (© 2021 Huang et al.)

The development of cationic polymers as non-viral gene vectors has been hurdled by their high toxicity, thus degradable and biocompatible polymers are urgently demanded. Herein, five polyesters (B3a-B3e) were synthesized based on the ring-opening copolymerization between α-allyl-δ-valerolactone and δ-valerolactone derivatives decorated with alkyl or alkoxyl chains of different lengths, followed by the modification with 1,5,9-triazacyclododecyl ([12]aneN 3 ) through thiol-ene click reactions. The five polyesters effectively condensed DNA into nanoparticles. Of them, B3a with a shorter alkyl chain and B3d with more positive charged units showed stronger DNA condensing performance and can completely retard the migration of DNA at N/P = 1.6 in the presence of DOPE. B3b/DOPE with a longer alkyl chain exhibited the highest transfection efficiency in HeLa cells with 1.8 times of 25 kDa PEI, while B3d/DOPE with more positive charged units exhibited highest transfection efficiency in A549 cells with 2.3 times of 25 kDa PEI. B3b/DOPE and B3d/DOPE successfully delivered pEGFP into zebrafish, which was superior to 25 kDa PEI (1.5 folds and 1.1 folds, respectively). The cytotoxicity measurements proved that the biocompatibility of these polyesters was better than 25 kDa PEI, due to their degradable property in acid environment. The results indicated that these cationic polyesters can be developed as potential non-viral gene vectors for DNA delivery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Carbon black nanoparticles (CBNPs) are one of the most frequently used nanoparticles. Exposure to CBNPs during pregnancy (PrE to CBNPs) can directly induce inflammation, lung injury, and genotoxicity in dams and results in abnormalities in offspring. However, whether exposure to CBNPs during pregnancy enhances the susceptibility of offspring to environmental stimuli remains unknown. To address this issue, in this study, we intranasally treated pregnant mice with mock or CBNPs from gestational day ( GD ) 9 to GD18 , and F1 and F2 offspring were normally obtained. By intratracheal instillation of mice with lipopolysaccharide (LPS) to trigger a classic animal model for acute lung injury, we intriguingly found that after LPS treatment, F1 and F2 offspring after exposure during pregnancy to CBNPs both exhibited more pronounced lung injury symptoms, including more degenerative histopathological changes, vascular leakage, elevated MPO activity, and activation of inflammation-related signaling transduction, compared with F1 and F2 offspring in the mock group, suggesting PrE to CBNPs would aggravate LPS-induced lung injury in offspring, and this effect was intergenerational. We also observed that PrE to CBNPs upregulated the mRNA expression of DNA methyltransferases (Dnmt) 1/3a/3b and DNA hypermethylation in both F1 and F2 offspring, which might partially account for the intergenerational effect. Together, our study demonstrates for the first time that PrE to CBNPs can enhance sensitivity to LPS in both F1 and F2 offspring, and this intergenerational effect may be related to DNA hypermethylation caused by CBNPs.

Background: Renal fibrosis is the common pathway in chronic kidney diseases progression to end-stage renal disease, but to date, no clinical drug for its treatment is approved. It has been demonstrated that the inhibitor of proto-oncogene Ras, farnesylthiosalicylic acid (FTS), shows therapeutic potential for renal fibrosis, but its application was hindered by the water-insolubility and low bioavailability. Hence, in this study, we improved these properties of FTS by encapsulating it into bovine serum albumin nanoparticles (AN-FTS) and tested its therapeutic effect in renal fibrosis., Methods: AN-FTS was developed using a classic emulsification-solvent ultrasonication. The pharmacokinetics of DiD-loaded albumin nanoparticle were investigated in SD rats. The biodistribution and therapeutic efficacy of AN-FTS was assessed in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO)., Results: AN-FTS showed a uniform spherical shape with the size of 100.6 ± 1.12 nm and PDI < 0.25. In vitro, AN-FTS displayed stronger inhibitory effects on the activation of renal fibroblasts cells NRK-49F than free FTS. In vivo, AN-FTS showed significantly higher peak concentration and area under the concentration-time curve. After intravenous administration to UUO-induced renal fibrosis mice, AN-FTS accumulated preferentially in the fibrotic kidney, and alleviated renal fibrosis and inflammation significantly more than the free drug. Mechanistically, the improved anti-fibrosis effect of AN-FTS was associated with greater inhibition in renal epithelial-to-mesenchymal transformation process via Ras/Raf1/p38 signaling pathway., Conclusion: The study reveals that AN-FTS is capable of delivering FTS to fibrotic kidney and showed superior therapeutic efficacy for renal fibrosis., Competing Interests: The authors declare no competing interests., (© 2021 Huang et al.)

Hypoxia in a solid tumor microenvironment (TME) can lead to the overexpression of hypoxia-inducible factor-1α (HIF-1α), which correlates to tumor metastasis. Reactive oxygen species (ROS) induced tumor cell apoptosis is becoming a promising method in tumor treatment. Currently, the ROS generating systems, e.g., photodynamic treatment and sonodynamic treatment, highly depend on oxygen (O 2 ) in the tumor microenvironment (TME). However, the level of O 2 in TME is too low to produce enough ROS. Herein, we developed an ultrasmall DSPE-PEG 2000 coated barium titanate nanoparticle (P-BTO) for tumor treatment based on ultrasound triggered piezocatalysis and water splitting. Interestingly, irradiated by ultrasound, the surface of ultasmall P-BTO nanoparticles produced imbalance charges, which induced a cascade of redox reaction processes to simultaneously generate ROS and O 2 , the latter one was hardly generated in large-sized barium titanate nanoparticles. The as-synthesized P-BTO reached the highest accumulation in the tumor site at 4 h after intravenous injection. The results showed that the produced O 2 significantly alleviated the hypoxia of TME to down-regulate the expression of HIF-1α, and the produced ROS can efficiently kill tumor cells. Moreover, the tumor metastasis was also inhibited, providing a different way to treat triple-negative breast cancer, which was easily metastatic and lacked effective treatments in the clinic.

In most cases, once nanoparticles (NPs) enter the blood, their surface is covered by biological molecules, especially proteins, forming a so-called protein corona (PC). As a result, what the cells of the body "see" is not the NPs as formulated by the chemists, but the PC. In this way, the PC can influence the effects of the NPs and even mask the desired effects of the NP components. While this can argue for trying to inhibit protein-nanomaterial interactions, encapsulating NPs in an endogenous PC may increase their clinical usefulness. In this review, we briefly introduce the concept of the PC, its formation and its effects on the behavior of NPs. We also discuss how to reduce the formation of PCs or exploit them to enhance NP functions. Studying the interactions between proteins and NPs will provide insights into their clinical activity in health and disease. STATEMENT OF SIGNIFICANCE: The formation of protein corona (PC) will affect the operation of nanoparticles (NPs) in vivo. Since there are many proteins in the blood, it is impossible to completely overcome the formation of PC. Therefore, the use of PCs to deliver drug is the best choice. De-opsonins adsorbed on NPs can reduce macrophage phagocytosis and cytotoxicity of NPs, and prolong their circulation in blood. Albumin, apolipoprotein and transferrin are typical de-opsonins. In present review, we mainly discuss how to optimize the delivery of nanoparticles through the formation of albumin corona, transferrin corona and apolipoprotein corona in vivo or in vitro., Competing Interests: Declaration of Competing Interest All authors declare that No conflict of interest exists., (Copyright © 2021. Published by Elsevier Ltd.)

Metastasis is the main cause of death in cancer patients. The efficacy of pharmacological therapy for cancer is limited by the heterogeneous nature of cancer cells and the lack of knowledge of microenvironments in metastasis. Evidence has shown that activated platelets possess both tumor-homing and metastasis-targeting properties via intrinsic cell adhesion molecules on platelets, and malaria protein VAR2CSA is able to specifically bind to oncofetal chondroitin sulfate, which is overexpressed on cancer cells with both epithelial and mesenchymal phenotypes. Inspired by these mechanisms, we developed a recombinant VAR2CSA peptide (rVAR2)-modified activated platelet-mimicking nanoparticles (rVAR2-PM/PLGA-ss-HA) by coating the surface of disulfide-containing biodegradable PLGA conjugate nanoparticles (PLGA-ss-HA) with an activated platelet membrane. The results demonstrated that the engineered 122 nm rVAR2-PM/PLGA-ss-HA inherited the innate properties of the activated platelet membrane and achieved enhanced homing to both primary and metastatic foci. The nanoparticles were endocytosed and responded to a high intracellular concentration of reduced glutathione, resulting in nanoparticle disintegration and the release of chemotherapeutic drugs to kill tumor cells. Thus, rVAR2-decorated activated platelet-targeting nanoparticles with controlled drug release provide a promising drug delivery strategy for efficient treatment of primary and metastatic cancer.

Nanoscale zinc oxide (n-ZnO) is widely used in personal care products and textiles, thus, it would likely be released into human sweat. To better evaluate the potential human health risks of n-ZnO, it is essential to understand its chemical transformations in physiological solutions, such as human sweat, and the resulting changes in the n-ZnO bioavailability. Here, two types of n-ZnO, ZnO nanoparticles (ZnO-NPs) and nanorod-based ZnO nanospheres (ZnO-NSs) were synthesized and incubated in 3 types of simulated sweat with different pH values and phosphate concentrations. The content of Zn 3 (PO 4 ) 2 in the transformed n-ZnO was quantified by selective dissolution of Zn 3 (PO 4 ) 2 in 0.35 M ammonia solution where 100% and 5.5% of Zn 3 (PO 4 ) 2 and ZnO were dissolved, respectively. The kinetics analysis indicated that by 24-48 h the content of Zn 3 (PO 4 ) 2 reached the maximum, being 15-21% at pH 8.0 and 45-70% at pH 5.5 or 4.3. Interestingly, no correlation was observed between the rate constants of Zn 3 (PO 4 ) 2 formation and the specific surface areas of n-ZnO, implying that chemical transformations from n-ZnO to Zn 3 (PO 4 ) 2 in the simulated sweat might not be simply attributed to dissolution and precipitation. Using a variety of characterization techniques, we demonstrated the formation of a ZnO‒Zn 3 (PO 4 ) 2 core-shell structure with the shell consisting of amorphous Zn 3 (PO 4 ) 2 at pH 8.0 and additionally of crystalline Zn 3 (PO 4 ) 2 and Zn 3 (PO 4 ) 2 •4H 2 O at pH 5.5 or 4.3. The phosphate-induced transformation of n-ZnO in the simulated sweat at pH 5.5 and 4.3 greatly reduced the antibacterial efficacy of n-ZnO through moderating the nanoparticle dissolution, indicating limited bioavailability of the NPs upon transformation. The results improve the understanding of the fate and hazards of n-ZnO., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is commonly used as an "in situ vaccine" to enhance the response rate of PD-1/PD-L1 antibodies. Unfortunately, the high cost and adverse effects of these antibodies, and the hypoxic state of solid tumors limits the efficacy of synergistic photodynamic-immunotherapy. Here, we developed a biomimetic nanoemulsion camouflaged with a PD-1-expressing cell membrane for synergistic photodynamic-immunotherapy against hypoxic breast tumors. The perfluorocarbon of the nanoemulsion could provide oxygen as the source of PDT against hypoxic tumors. Moreover, co-delivering a photosensitizer and the PD-1 protein (substituting for a PD-L1 antibody) achieves the synergy effect of PDT and immunotherapy. Synergistic photodynamic-immunotherapy completely inhibited primary and distant subcutaneous 4T1 tumors, mechanistically by boosting the maturation of dendritic cells and tumor infiltration of cytotoxic T lymphocytes., (© 2021 Wiley-VCH GmbH.)

Polydopamine (PDA) has shown great potentials in biomedical fields due largely to its unique physicochemical properties, including high photothermal transfer efficiency, excellent drug binding capacity, versatile adhesion ability, sensitive pH responsibility and great biocompatibility and biodegradability. These properties confer PDA-based nanoparticles the potentials either as the drug carriers for advanced drug delivery or as the bioactive agents for photothermal therapy, imaging and biosensing. This review aims to provide a comprehensive understanding of PDA, its polymerization mechanisms and the potentials of PDA-based nano-systems in treating various diseases, including cancer, diabetes, inflammation, bacterial infection and Parkinson's disease. In addition, the concerns of PDA in biomedical use are also discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Flower-like metal-organic frameworks (Cu-MOF) nanoparticles are successfully synthesized and incorporated into cellulose acetate (CA) matrix to prepare CA-based functional nanocomposite films via a simple solution-casting method. The effect of the incorporation of flower-like Cu-MOF on the morphological, mechanical, thermal, surface wettability, water vapor barrier, cytotoxicity, photostability and UV-shielding properties of CA films is fully investigated. Results reveal that the flower-like Cu-MOF has good compatibility with CA, providing uniform and compact nanocomposite films. The as-prepared nanocomposite films show improved mechanical properties, surface hydrophobicity, water vapor barrier ability compared to neat CA film, and exhibit super UV-shielding capability through the entire UV regions meanwhile retaining a high visible transparency. Moreover, the high transparency and UV-shielding ability of the nanocomposite films can be still maintained even after continuous UV-light (365 nm) irradiation for 12 h. In addition, MTT cytotoxicity assays towards normal human liver cells (HL-7702) reveal high cell viability (over 80%) and good biocompatibility for the CA/Cu-MOF nanocomposite films. These results indicate that the CA/Cu-MOF nanocomposite films with obviously improved physical and functional performances hold significant potential for transparent packaging and UV-protection applications., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Platelet lysate (PL) as a cost-effective cocktail of growth factors is an emerging ingredient in regenerative medicine, especially in cartilage tissue engineering. However, most studies fail to pay attention to PL's intrinsic characteristics and incorporate it directly with scaffolds or hydrogels by simple mixture. Currently, the particle size distribution of PL was determined to be scattered. Directly introducing PL into a thermosensitive poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PLEL) hydrogel disturbed its sol-gel transition. Electrostatic self-assembly heparin (Hep) and ε-poly-l-lysine (EPL) nanoparticles (NPs) were fabricated to improve the dispersity of PL. Such PL-NPs-incorporated PLEL gels retained the initial gelling capacity and showed a long-term PL-releasing ability. Moreover, the PL-loaded composite hydrogels inhibited the inflammatory response and dedifferentiation of IL-1β-induced chondrocytes. For in vivo applications, the PLEL@PL-NPs system ameliorated the early cartilage degeneration and promoted cartilage repair in the late stage of osteoarthritis. RNA sequencing analysis indicated that PL's protective effects might be associated with modulating hyaluronan synthase 1 (HAS-1) expression. Taken together, these results suggest that well-dispersed PL by Hep/EPL NPs is a preferable approach for its incorporation into hydrogels and the constructed PLEL@PL-NPs system is a promising cell-free and stepwise treatment option for cartilage tissue engineering., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Increasing occupational and accidental exposure to carbon black nanoparticles (CBNPs) raise concerns over their possible effects on the nervous system. However, the influences of CBNPs on the neurodevelopment remain unclear. Thus, in this study, pregnant mice were exposed to different doses of CBNPs by intranasal instillation on gestation days 9-18. Our results demonstrated that maternal exposure to CBNPs caused significant changes on maternal behaviors. Pregnancy exposure to CBNPs also delayed the onset of incisor eruption, testes descent and vaginal opening in offspring, and caused the reduced body weight until adulthood. In the neurobehavioral tests, CBNPs-exposed offspring exhibited the elevated latency of negative geotaxis and surface right reflex, reduced grasping time and increased cliff avoidance. Histopathological changes were present in F1 generation but not in F2 generation. Intriguingly, our data revealed that the levels of total m 6 A modification were significantly decreased by CBNPs. Similar trends were observed on the mRNA expressions of m 6 A methyltransferases and demethylases. In summary, these findings provide the novel evidence that pregnancy exposure to CBNPs affects the maternal behaviors and partially induces the neurobehavioral, muscular and histopathological changes in offspring. Of note, these adverse effects may be associated with reduced levels of total m 6 A modification in brain., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Previously, we have demonstrated the use of lipidoid (lipid-like) nanoparticles (e.g., "1-O16B") for gene delivery to live cells, as an alternative to viral vectors. Here, we encapsulate VEGF siRNA (siVEGF) in bioreducible lipidoid nanoparticles and examine whether these nanocomplexes can reduce intravitreal neovascularization in a rodent model of oxygen-induced retinopathy (OIR)., Methods: Firstly, we constructed siVEGF-nanoparticles (NPs) and transfected human umbilical vein endothelial cells, which caused significantly reduced expression of VEGF, compared to exposure to siVEGF in solution. Secondly, we compared the effect of intravitreal siVEGF-NPs and an anti-VEGF drug (ranibizumab) on retinal vascular development and VEGF mRNA/protein expression in the retinas of a rat model of OIR., Results: Compared to a non-functional lipid vehicle control group, the level of VEGF mRNA and protein was significantly lower in the siVEGF-NP group (p < 0.01), but the level of VEGF mRNA was not significantly lower in the ranibizumab group. Anatomically, the number of retinal neovascular endothelial nuclei that had protruded through the internal limiting membrane and the number of areas of non-perfusion of the retina were both significantly lower in the siVEGF-NP group and the ranibizumab group than in the OIR group (p < 0.01)., Conclusion: Our results demonstrate that bioreducible lipidoid nanoparticles conveying VEGF siRNA can effectively inhibit retinal neovascularization in a rodent model of OIR, and reduce the expression of VEGF mRNA and protein. This novel treatment modality could have profound implications for treating retinal angiogenic diseases.

Commercially available drug-eluting embolization beads (100-500 μm) reduced the occurrence of adverse events related to an anticancer drug, but were unascertained to remarkably benefit the transcatheter arterial chemoembolization (TACE) treatment of intermediate-stage liver cancer. Dextran-coated arsenite nanoparticles with the size ranging from 400 to 600 nm were developed as a nanosized drug-eluting bead (NDEB) for chemoembolization therapy of the rabbit VX2 liver tumor. We fully characterized their relevant physicochemistry and drug release properties. Their hemolysis was investigated before vessel embolization. The introduction of the NDEB allowed continuous embolization of tumor feeding vessels and sustained release of arsenic trioxide, thereby causing severe tumor necrosis and reduced vascularity. Sonography including B mode ultrasound, color Doppler flow imaging (CDFI) and dynamic contrast-enhanced ultrasound (CEUS) were performed to evaluate the tumor vascularity and viability. Additionally, its hepatotoxicity was tolerable at a medium dose. NDEB-TACE might be an effective therapeutic strategy for interventional therapy.

Background: Cell-bound membrane vesicles (CBMVs) are a type of membrane vesicles different from the well-known extracellular vesicles (EVs). In recent years, the applications of EVs as drug delivery systems have been studied widely. A question may arise whether isolated CBMVs also have the possibility of being recruited as a drug delivery system or nanocarrier?, Methods: To test the possibility, CBMVs were isolated/purified from the surfaces of cultured endothelial cells, loaded with a putative antitumor drug doxorubicin (Dox), and characterized. Subsequently, cellular experiments and animal experiments using mouse models were performed to determine the in vitro and in vivo antitumor effects of Dox-loaded CBMVs (Dox-CBMVs or Dox@CBMVs), respectively., Results: Both Dox-free and Dox-loaded CBMVs were globular-shaped and nanometer-sized with an average diameter of ~ 300-400 nm. Dox-CBMVs could be internalized by cells and could kill multiple types of cancer cells. The in vivo antitumor ability of Dox-CBMVs also was confirmed. Moreover, Quantifications of blood cells (white blood cells and platelets) and specific enzymes (aspartate aminotransferase and creatine kinase isoenzymes) showed that Dox-CBMVs had lower side effects compared with free Dox., Conclusions: The data show that the CBMV-entrapped Doxorubicin has the antitumor efficacy with lower side effects. This study provides evidence supporting the possibility of isolated cell-bound membrane vesicles as a novel drug nanocarrier.

In this study, amphiphilic conjugates were synthesized by conjugating curcumin (CUR) to a food-derived hydrophilic hydroxyethyl starch (HES) via an acid-labile ester linker. The self-assembly of the conjugates formed uniform micellar nanoparticles (HES-CUR NPs) with a desirable drug loading efficiency, excellent colloidal and storage stability, as well as acid-responsive release manner. Besides, the formation of the nanoparticles increased the solubility of CUR to thousands times higher than free CUR, and effectively protected the loaded CUR from degradation upon exposure to UV light and high temperature. In vitro cytotoxicity assay and radical scavenging experiments demonstrated that the HES-CUR NPs significantly improved the cytocompatibility, anticancer and antioxidant activity of CUR due to the enhanced solubility, stability, and bioavailability. The HES-CUR NPs reported herein have a great potential in developing functional food or pharmaceutical formulations for preventing or treating various diseases such as inflammatory diseases and cancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Arsenic trioxide (ATO) has remarkably enhanced therapeutic efficacy in treating both newly diagnosed and relapsed patients suffering from Acute Promyelocytic Leukemia (APL). Unfortunately, whether as a single agent, component of combined chemotherapy, or as a chemosensitizer or radiosensitizer combined with interventional therapy/radiotherapy, it did not benefit treatment of solid tumor (liver cancer, bladder cancer, glioma, breast cancer, cervical cancer, colorectal cancer, lung cancer, and melanoma) as seen from the clinical trials reported from the published journals or FDA-approved trials in the past decades. The clinical outcome failed to live up to our expectations, which was attributed to severe systemic toxicity and inappropriate pharmacokinetic such as low delivery efficiency and rapid renal elimination. Nanomedicine is designed to fuel up pharmaceuticals and polish off adverse effects by the moderation of their absorption, distribution, metabolism, and excretion. Nevertheless, quite a few nanodrugs (such as Doxil, Abraxane) were approved to be used clinically, and "from bench to bedside" it seems to be no easy way for most of them, such as nano-ATO. Encapsulating ATO into several types of nano-vehicles (liposome, polymer micelle, porous silicon, etc.), nano-TO can improve pharmacokinetic and become a prominent candidate to penetrate into tumor tissue, but so far no nano- ATO clinical trials have been approved around the world. On summarizing the clinical trials of ATO on solid tumor and preclinical study of nano-ATO, it is believed there is still a chance for ATO to play a critical co-helper in a comprehensive therapy to fight with solid tumor., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Messenger RNA (mRNA) represents an emerging class of nucleic acid therapeutics for genome editing and genetic disease treatment. Delivering exogenous mRNA selectively to cells, however, remains a main challenge to broaden the biomedical application of mRNA and develop targeted gene therapy. Herein, we report cell-selective mRNA delivery and CRISPR/Cas9 genome editing by modulating the interface of phenylboronic acid (PBA) derived lipid nanoparticles (NPs) and cellular surface sialic acid (SA). We design a cationic lipid featuring a PBA group, PBA-BADP, to self-assemble with mRNA into nanoparticles via electrostatic interactions. Importantly, these nanoparticles present free PBA groups on their surface, showing an enhanced cellular uptake by SA-overexpressing cancer cells via the interfacial PBA/SA interaction. It is shown that PBA-BADP/mRNA NPs transfection results in 300 times higher luciferase reporter gene expression in cancer cells than that in noncancer cells. Moreover, we demonstrate that the delivery of tumor suppressor p53 mRNA using PBA-BADP selectively prohibits cancer cell growth, while PBA-BADP/Cas9 mRNA NPs delivery knocks out gene expression of HeLa cancer cells in a much higher efficiency than noncancer cells. We believe these findings could further extend the modulation of PBA and cellular SA interface to advance mRNA delivery and genome editing for new gene therapy.

Paclitaxel (Ptx) is a first-line chemotherapeutic drug for advanced gastric cancer. However, the poor solubility of Ptx still limits its clinical application. Here, we designed a methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) (DSPE-PEG 2000 -TK-Ptx) nanoparticle loaded with "ROS sensitive" groups-thioketal (TK) to improve Ptx release in high ROS areas in cells. We evaluated the anticancer effect of the DSPE-PEG 2000 -TK-Ptx nanoparticles (Ptx-NPs) in the SGC-7901 gastric tumor cell line. The Ptx-NPs-treated group showed superior cytotoxicity to the same dose of free Ptx by MTT test and clonogenic assay. Autophagy inhibitor 3-MA protected cells from the cytotoxicity of Ptx in tumor cells. More autophagic cells were identified in the Ptx-NPs group via MDC/EB dual staining. NAC, an ROS inhibitor, inhibited cell autophagy induced by free Ptx or Ptx-NPs. SGC-7901 cells transfected with mCherry-EGFP-LC3II showed much brighter fluorescence in the Ptx-NPs group, while 3-MA markedly suppressed the fluorescence. Western blot verified the protein expression of autophagy, such as P62, Beclin 1 and LC3II. In this study, "ROS sensitive" conjugated DSPE-PEG 2000 -TK-Ptx nanoparticles with enhanced cancer-suppressive efficacy were produced. Ptx-NPs could be a promising antitumor agent for gastric cancer treatment with more efficiency and fewer side effects.