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The formation of protein corona (PC) is important for promoting the in vivo delivery of nanoparticles (NPs). However, PC formed in the physiological environment of oral delivery is poorly understood. Here, we engineered seven types of trimethyl chitosan-cysteine (TC) NPs, with distinct molecular weights, quaternization degrees, and thiolation degrees, to deeply investigate the influence of various PC formed in the physiological environment of oral delivery on in vivo gene delivery of polymeric NPs, further constructing the relationship between the surface characteristics of NPs and the efficacy of oral gene delivery. Our findings reveal that TC7 NPs, with high molecular weight, moderate quaternization, and high sulfhydryl content, modulate PC formation in the gastrointestinal tract, thereby reducing particle size and promoting oral delivery of gene loaded TC7 NPs. Orally delivered TC7 NPs target macrophages by in situ adsorption of apolipoprotein (Apo) B48 in intestinal tissue, leading to the improved in vivo antihepatoma efficacy via the natural tumor homing ability of macrophages. Our results suggest that efficient oral delivery of genes can be achieved through an in situ customized ApoB48-enriched PC, offering a promising modality in treating macrophage-related diseases., 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 Ltd. All rights reserved.)

Zika virus (ZIKV) is a mosquito-borne flavivirus that highly susceptibly causes Guillain-Barré syndrome and microcephaly in newborns. Vaccination is one of the most effective measures for preventing infectious diseases. However, there is currently no approved vaccine to prevent ZIKV infection. Here, we developed nanoparticle (NP) vaccines by covalently conjugating self-assembled 24-subunit ferritin to the envelope structural protein subunit of ZIKV to achieve antigen polyaggregation. The immunogenicityof the NP vaccine was evaluated in mice. Compared to monomer vaccines, the NP vaccine achieved effective antigen presentation, promoted the differentiation of follicular T helper cells in lymph nodes, and induced significantly greater antigen-specific humoral and cellular immune responses. Moreover, the NP vaccine enhanced high-affinity antigen-specific IgG antibody levels, increased secretion of the cytokines IL-4 and IFN-γ by splenocytes, significantly activated T/B lymphocytes, and improved the generation of memory T/B cells. In addition, no significant adverse reactions occurred when NP vaccine was combined with adjuvants. Overall, ferritin-based NP vaccines are safe and effective ZIKV vaccine candidates., 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.)

Triple-negative breast cancer (TNBC) is known for its strong invasiveness, high recurrence rates, and poor prognosis. Heme oxygenase-1 (HO-1) is closely related to tumor invasion, metastasis, recurrence and formation of tumor immunosuppression. The expression of HO-1 is high in TNBC and low in normal tissues. In this study, AgPPIX was synthesized as a heme oxygenase-1 (HO-1) inhibitor and a photosensitizer for TNBC therapy. PDA nanoparticles were synthesized and modified with anti-CD24 and p -toluenesulfonamide (PTSC) on their both sides to obtain PTSC@AgPPIX/PDA@anti-CD24 Janus nanoparticles (PAPC) for AgPPIX-targeted delivery. Anti-CD24 is targeted to CD24 on tumor cells and the PTSC moiety is targeted to endoplasmic reticulum (ER), where HO-1 is located. The results indicated that PAPC Janus nanoparticles exhibited higher cytotoxicity in 4T1 cells than that of the mono-modified nanoparticles. PAPC not only inhibited the expression of HO-1 and VEGF but also reduced TrxR activity significantly. Furthermore, PAPC not only promoted intracellular ROS production under laser irradiation for tumor photodynamic therapy (PDT) but also polarized TAMs from M2-type to M1 for tumor immunotherapy. In vivo experiments confirmed that PAPC could remodel the tumor immune microenvironment and almost completely inhibit the tumor growth in mouse models. Therefore, PAPC Janus nanoparticles are a promising nanoplatform with a dual-targeting capacity for TNBC immune/PDT synergistic therapy.

Targeting nanoparticles (NPs) based on the specific binding of ligands with molecular targets provides a promising tool for tissue-selective drug delivery. However, the number of molecular targets on the cell surface is limited, hindering the number of NPs that can bind and, thus, limiting the therapeutic outcome. Although several strategies have been developed to enhance drug delivery, such as enhancing drug loading and circulation time or increasing the enhanced permeability and retention effect of nanocarriers, none have resolved this issue. Herein, we designed a simple method for amplified and targeted drug delivery using two matched NPs. One NP was aptamer-functionalized to specifically bind to target cells, while the other was aptamer-complementary DNA-functionalized to specifically bind to aptamer-NPs. Alternate administration of the two matched NPs enables their continuous accumulation in the disease site despite their limited molecular targets. As a proof of concept, the method was tested in a breast cancer model and significantly enhanced chemotherapy of tumor cells in vitro and in vivo . The potential applications of this method in a brain injury model were also demonstrated. Overall, the study describes a method for amplified targeted drug delivery independent of the target number.

MicroRNA (miRNA) has been widely used as an effective gene drug for tumor therapy, but its chemical instability limited its therapeutic application in vivo. In this research, we fabricate an efficient miRNA nano-delivery system using zeolitic imidazolate framework-8 (ZIF-8) coated with bacterial outer membrane vesicles (OMVs), aimed for cancer treatment. The acid-sensitive ZIF-8 core enables this system to encapsulate miRNA and release them from lysosome quickly and efficiently in the target cells. The OMVs engineered to display programmed death receptor 1 (PD1) on the surface provides a specific tumor-targeting capability. Using a murine breast cancer model, we show that this system has high miRNA delivery efficiency and accurate tumor targeting. Moreover, the miR-34a payloads in carriers can further synergize with immune activation and checkpoint inhibition triggered by OMV-PD1 to enhance tumor therapeutic efficacy. Overall, this biomimetic nano-delivery platform provides a powerful tool for the intracellular delivery of miRNA and has great potential in RNA-based cancer therapeutic applications., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Most anticancer treatments only induce the death of ordinary cancer cells, while cancer stem cells (CSCs) in the quiescent phase of cell division are difficult to kill, which eventually leads to cancer drug resistance, metastasis, and relapse. Therefore, CSCs are also important in targeted cancer therapy. Herein, we developed dual-targeted and glutathione (GSH)-responsive novel nanoparticles (SSBPEI-DOX@siRNAs/iRGD-PEG-HA) to efficiently and specifically deliver both doxorubicin and small interfering RNA cocktails (siRNAs) (survivin siRNA, Bcl-2 siRNA and ABCG2 siRNA) to ovarian CSCs. They are fabricated via electrostatic assembly of anionic siRNAs and cationic disulfide bond crosslinking-branched polyethyleneimine-doxorubicin (SSBPEI-DOX) as a core. Interestingly, the SSBPEI-DOX could be degraded into low-cytotoxic polyethyleneimine (PEI). Because of the enrichment of glutathione reductase in the tumor microenvironment, the disulfide bond (-SS-) in SSBPEI-DOX can be specifically reduced to promote the controlled release of siRNA and doxorubicin (DOX) in the CSCs. siRNA cocktails could specifically silence three key genes in CSCs, which, in combination with the traditional chemotherapy drug DOX, induces apoptosis or necrosis of CSCs. iRGD peptides and "sheddable" hyaluronic acid (HA) wrapped around the core could mediate CSC targeting by binding with neuropilin-1 (NRP1) and CD44 to enhance delivery. In summary, the multifunctional delivery system SSBPEI-DOX@siRNAs/iRGD-PEG-HA nanoparticles displays excellent biocompatibility, accurate CSC-targeting ability, and powerful anti-CSC ability, which demonstrates its potential value in future treatments to overcome ovarian cancer metastasis and relapse. To support this work, as exhaustive search was conducted for the literature on nanoparticle drug delivery research conducted in the last 17 years (2007-2023) using PubMed, Web of Science, and Google Scholar.

Hypoparathyroidism (HypoPT) is a rare disease involving the parathyroid glands that is characterized by a reduced secretion or potency of the parathyroid hormone (PTH), which leads to high serum phosphorus levels and low serum calcium levels. HypoPT most commonly results from accidental damage to the glands or their removal during thyroid or other anterior neck surgery. Parathyroid/thyroid surgery has become more common in recent years, with a corresponding rise in the occurrence of HypoPT as a postoperative complication. There is a critical need for a HypoPT animal model to better understand the mechanisms underlying the effects of HypoPT on mineral ion homeostasis and to verify the therapeutic effectiveness of novel treatments. Here, a technique is reported to create acquired HypoPT in male rats by performing parathyroidectomy (PTX) using carbon nanoparticles. The rat model shows great promise over the mouse models of hypoparathyroidism. Importantly, the human PTH receptor binding region has an 84.2% sequence similarity with that of the rat, which is higher than the 73.7% similarity shared with mice. Moreover, the effects of estrogen, which can affect the PTH/PTHrP receptor signaling pathway, have not been fully investigated in male rats. Carbon nanoparticles are lymphatic tracers that stain the thyroid lymph nodes black without affecting their function, but they do not stain the parathyroid glands, which makes them easy to identify and remove. In this study, serum PTH levels were undetectable after PTX, and this resulted in significant hypocalcemia and hyperphosphatemia. Thus, the clinical state of postoperative HypoPT can be remarkably represented in the rat model. Carbon-nanoparticle-assisted PTX can, therefore, serve as an extraordinarily effective and readily implementable model for studying the pathogenesis, treatment, and prognosis of HypoPT.

The effectiveness of the commonly used therapy is low for treating triple-negative breast cancer (TNBC). Macrophages, accounting for up to 50% of the TNBC tumor mass, are involved in innate and adaptive immunity, which can serve as an effective weapon against TNBC via combined immunotherapy. Here, we engineered mannose and glycocholic acid-modified trimethyl chitosan (MTG) nanoparticles (NPs) encapsulating signal regulatory protein α (SIRPα) siRNA (siSIRPα, a macrophage checkpoint inhibitor) and mucin 1 (MUC1) pDNA (pMUC1, a therapeutic pDNA vaccine) (MTG/siSIRPα/pMUC1 NPs) for in situ educating macrophages via an oral route to exert the cooperative antitumor effects of siSIRPα and pMUC1. Orally delivered MTG-based NPs accumulated in the macrophages in lymph nodes and tumor tissues via the intestinal lymphatic transport pathway, leading to strong cellular immunity responses. Following the transfection of orally administered MTG/siSIRPα/pMUC1 NPs within the same macrophages, siSIRPα strengthened the pMUC1 vaccine-induced systemic cellular immunity, while pMUC1 enhanced siSIRPα-mediated macrophage phagocytosis, M1-phenotype polarization, and tumor microenvironment (TME) remodeling at the tumor sites, thereby inhibiting the growth and metastasis of TNBC. The simultaneous achievements of the mutual promotion of innate and adaptive immunity in the local TME and in the whole body suggested that MTG/siSIRPα/pMUC1 NPs would provide a promising paradigm for the combined immunotherapy of TNBC via oral delivery of genes.

Polymeric micelles are extensively studied nanocarriers to improve the solubility, blood circulation, biodistribution, and adverse effects of chemotherapeutic drugs. However, the antitumor efficacy of polymeric micelles is often restricted due to multiple biological barriers, including blood fluid shear stress (FSS) and limited tumor penetration in vivo. Herein, cellulose nanocrystal (CNC) as a green material with rigidity and rod-shaped structure is developed to be an enhancing core for polymeric micelles to overcome these biological barriers. Doxorubicin (DOX) loaded methoxy poly (ethylene glycol)-block-poly (D, L-lactic acid) (mPEG-PLA, PP) ligated CNC nanoparticles (PPC/DOX NPs) are fabricated via one-pot synthesis. In comparison to the self-assembled DOX loaded mPEG-PLA micelles (PP/DOX NPs), PPC/DOX NPs exhibit remarkable improvements in FSS resistance, cellular internalization, blood circulation, tumor penetration, and antitumor efficacy owing to the unique rigidity and rod-shaped structure of CNC core. Moreover, PPC/DOX NPs present various advantages beyond DOX·HCl and CNC/DOX NPs. The superiority of PPC/DOX NPs in antitumor efficacy reveals the effectiveness of adopting CNC as the enhancing core for polymeric micelles, suggesting that CNC is a promising biomaterial in advancing nanomedicine., 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.)

Photothermal therapy (PTT) in combination with other treatment modalities has shown great potential to activate immunotherapy against tumor metastasis. However, the nanoparticles (NPs) that generate PTT have served as the photothermal agent only. Moreover, researchers have widely utilized highly immunogenic tumor models to evaluate the immune response of these NPs thus giving over-optimistic results. In the present study black porous silicon (BPSi) NPs were developed to serve as both the photothermal agent and the adjuvant for PTT-based antitumor immunotherapy. We found that the poorly immunogenic tumor models such as B16 are more valid to evaluate NP-based immunotherapy than the widely used immunogenic models such as CT26. Based on the B16 cancer model, a cocktail regimen was developed that combined BPSi-based PTT with doxorubicin (DOX) and cytosine-phosphate-guanosine (CpG). BPSi-based PTT was an important trigger to activate the specific immunotherapy to inhibit tumor growth by featuring the selective upregulation of TNF-α. Either by adding a low dose DOX or by prolonging the laser heating time, a similar efficacy of immunotherapy was evoked to inhibit tumor growth. Moreover, BPSi acted as a co-adjuvant for CpG to significantly boost the immunotherapy. The present study demonstrates that the BPSi-based regimen is a potent and safe antitumor immunotherapy modality. Moreover, our study highlighted that tuning the laser heating parameters of PTT is an alternative to the toxic cytostatic to evoke immunotherapy, paving the way to optimize the PTT-based combination therapy for enhanced efficacy and decreased side effects. STATEMENT OF SIGNIFICANCE: Tumor metastasis causes directly or indirectly more than 90% of cancer deaths. Combination of photothermal therapy (PTT), chemotherapy and immunotherapy based on nanoparticles (NPs) has shown great potential to inhibit distant and metastatic tumors. However, these NPs typically act only as photothermal agents and many of them have been evaluated with immunogenic tumor models. The present study developed black porous silicon working as both the photothermal conversion agent and the immunoadjuvant to inhibit distant tumor. It was recognized that the poorly immunogenic tumor model B16 is more appropriate to evaluate immunotherapy than the widely used immunogenic model CT26. The coordination mechanism of the PTT-based combination therapy regimen was discovered in detail, paving the way to optimize cancer immunotherapy for enhanced efficacy and decreased side effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The combination of phototherapy and chemotherapy has received extensive attention in the field of cancer therapy. Hence, graphene organic framework (GOF) with a large d-spacing was prepared by solvothermal method, and a novel nanocomposite based on bovine serum albumin (BSA) and the anticancer drug doxorubicin (DOX) was developed, which effectively achieved a photothermal-chemotherapy synergistic treatment. When the feeding ratio was 1:1.6, the DOX loading capacity was 18.51%, and the GOF-BSA/DOX nanocomposite possessed unobvious pH response characteristic, as well as the cumulative release of DOX reached 54.17% at 42°C in the acidic environment (pH = 5.0). The nanocarriers also showed excellent photothermal property and photothermal stability in vitro. In addition, under 808 nm near-infrared laser (NIR) irradiation, the GOF-BSA/DOX nanocomposites generated a large amount of heat, which significantly enhanced the synergistic antitumor effect of in vitro photothermal-chemotherapy. Furthermore, the GOF-BSA/DOX nanocomposites exhibited significantly increased cytotoxicity in the NIR compared with chemotherapy or photothermal therapy alone, suggesting that the combination of chemotherapy and photothermal therapy has excellent antitumor capacity. Therefore, porous GOF nanocarriers may have great potential in combined anti-tumour therapy.

Antigen proteins, assembled on nanoparticles, can be recognized by antigen-presenting cells effectively to enhance antigen immunogenicity. The ability to simultaneously display multiantigens on the same nanoparticle could have numerous applications but remained technical challenges. Here, we described a method for precise assembly of multiple antigens on nanoparticles with specially designed affinity peptides. First, we designed and screened affinity peptides with high affinity and specificity, which could respectively target the key amino acid residues of classical swine fever virus (CSFV) E2 protein or porcine circovirus type 2 capsid protein (PCV2 Cap) accurately. Then, we conjugated the antigen proteins to poly(lactic acid-glycolic acid) copolymer (PLGA) and Gram-positive enhancer matrix (GEM) nanoparticles through the peptides and perfectly assembled two kinds of multiantigen display nanoparticles with different particle sizes. Subsequently, the immunological properties of the assembled nanoparticles were tested. The results showed that the antigen display nanoparticles could promote the maturation, phagocytosis, and proinflammatory effects of antigen-presenting cells (APCs). Besides, compared with the antigen proteins, multiantigen display nanoparticles could induce much higher levels of antibodies and neutralizing antibodies in mice. This strategy may provide a technical support for the study of protein structure and the research and development of polyvalent vaccines.

Ferroptosis is a newly found cell death mechanism, which could bypass apoptosis and reverse multidrug resistance of tumors. However, efficient induction of tumor ferroptosis remains a challenge. In this study, multifunctional "ball-rod" Janus nanoparticles (FTG/L&SMD) were constructed for non-small cell lung cancer (NSCLC) ferroptosis treatment. Protected by tannic acid (TA), FTG/L&SMD maintains long-term function in blood circulation, while modification by 2, 3-dimethylmaleic anhydride (DMMA) confers the FTG/L&SMD with pH-responsive charge reversal. Glucose oxidase (GOD) on FTG/L&SMD catalyzes glucose to produce H 2 O 2 . Then, iron ion converts H 2 O 2 to highly active hydroxyl radicals (OH•) via Fenton reaction, leading to lethal lipid peroxidation (LPO) accumulation. Meanwhile, TA reduces Fe 3+ to Fe 2+ to boost Fenton reaction cycle. Sor down-regulated glutathione peroxidase 4 (GPX4) expression in another pathway to induce ferroptosis synergistically. In vitro studies have shown that compared with sorafenib (Sor), FTG/L&SMD not only has more efficient tumor targeting and higher cytotoxicity, but also inhibits tumor migration. In vivo antitumor therapy experiments demonstrate that FTG/L&SMD inhibits tumor growth efficiently, and its toxicity is negligible. In general, FTG/L&SMD can initiate Fenton reaction cycle and reinforced ferroptosis to kill tumor cells, which is a promising anti-tumor nano-drug for NSCLC., 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 Inc. All rights reserved.)

Mitochondria as one of the key subcellular organelles have been well recognized as a promising druggable target and are closely associated with energy supply and various cellular functions. Realizing high accumulation and prolonged retention of radiosensitizers in the cellular mitochondria of tumors is an effective way to improve radiotherapeutic efficacy. Herein, we develop mitochondria-targeting and protein sulfenic acid (PSA)-reactive gold nanoparticles (dAuNP-TPP) that are fabricated by incorporating triphenylphosphine and 1,3-cyclohexanedione onto the surface of AuNPs (∼20 nm) to improve CT imaging and radiotherapeutic efficacy of tumors. Taking advantage of the specific mitochondrial targeting and PSA-mediated on-site covalent immobilization, this nanosystem shows significantly enhanced accumulation and retention in mitochondria with approximately 5.22-fold higher enrichment than nonimmobilizable AuNP-TPP. More notably, the covalent immobilization of dAuNP-TPP in cellular mitochondria could induce a dramatic reduction of ATP, leading to serious mitochondrial disruption, combined with the radiosensitization effect, in consequence achieving efficient radiotherapy of breast tumors in vivo. This subcellular organelle-targeted and immobilizable strategy may offer a valuable and universal tool for efficient tumor treatment.

Folic acid (FA) and 2-(Diisopropylamino) ethyl methacrylate (DPA) double grafted trimethyl chitosan (TMC) nanoparticles (FTD NPs) were synthesized for the co-delivery of doxorubicin (DOX) and Survivin CRISPR/Cas9-expressing plasmid (sgSurvivin pDNA) or Survivin shRNA-expressing plasmid (iSur pDNA). FA modification enhanced the uptake of DOX and pDNA loaded into FTD NPs in tumor cells. A rapid release of DOX was triggered under acidic conditions due to pH-sensitiveness of FTD NPs arising from DPA conjugation. Negligible differences between FTD/sgSurvivin pDNA NPs and FTD/iSur pDNA NPs demonstrated that RNA interference (RNAi) and CRISPR/Cas9 technologies possessed comparable antitumor efficiency. Notably, the in vitro and in vivo antitumor efficacies of FTD/DOX/sgSurvivin pDNA NPs were superior to those of single delivery of DOX or sgSurvivin pDNA, while were comparable to those of FTD/DOX/iSur pDNA NPs. These results suggested that the combination of chemotherapeutics and CRISPR/Cas9 systems would provide a potential modality for cancer therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ferroptosis is a newly found promising cell death pathway, which bypasses apoptosis and overcomes multidrug resistance of tumor. In this study, acid and redox dual-responsive multifunctional magnetic nanoparticles loading with Sorafenib (Sor), namely FMMHG/Sor, were prepared for tumor ferroptosis therapy. Fe 3 O 4 nanoparticles as the core provided sufficient iron ion for ferroptosis and magnetic targeting. Mesoporous organosilica nanoparticles (MON) was coated on the outside of Fe 3 O 4 to form "core-shell" structure, which contained the disulfidebond with redox-responsive. MnO 2 was dropped on the surface of MON as gatekeeper, which was decomposed at low pH into O 2 to promote drug release. Glucose oxidase (GOD) catalyzed glucose to produce H 2 O 2 , which reacted with iron ion to generate hydroxylradical (OH•) vie Fenton reaction. OH• inhibited GPX4 expression to induce ferroptosis with Sor as a synergistic inducer. Hyaluronic acid (HA) protected nanoparticles from removed by immune system and actively targeted to tumor cells. Overall, pH and redox dual-responsive FMMHG/Sor is a promising antitumor nanomedicine with magnetic targeting and active targeting for efficient tumor ferroptosis therapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This work was to evaluate the therapeutic effect of lipid nanoparticle-loaded sorafenib combined with transcatheter artery chemoembolization (TACE) in patients with primary hepatocellular carcinoma (HC) complicated with microvascular invasion (MVI). In this work, 102 patients with primary HC combined with MVI after radical resection were divided into 4 groups according to different treatment methods. Experimental group 1 was treated with lipid nanoparticle-loaded sorafenib combined with TACE treatment group; experimental group 2 was treated with lipid nanoparticle-loaded sorafenib treatment group; experimental group 3 was TACE treatment group; control group was postoperative routine nursing group. Sorafenib lipid nanoparticles were prepared. The basic information, operation, MVI degree, tumor recurrence, and survival time of patients in each group were recorded and compared to evaluate the therapeutic effect of combined way. No great difference was found in MVI grade, average age, sex ratio, preoperative tumor markers, tumor size, number of patients with liver cirrhosis, operation time, and intraoperative bleeding among the four groups ( P > 0.05). In addition, the tumor free survival time (TFST), overall survival time (OST), and postoperative 1-year and 2-year survival rates of patients in test group 1 were greatly higher than those in single mode treatment group and control group ( P < 0.05). In summary, sorafenib nanoparticles combined with TACE can improve the survival status of patients after resection and delay the time of postoperative tumor recurrence., Competing Interests: The authors declare that they have no competing interest., (Copyright © 2022 Wendong Feng et al.)

Background: Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), has evolved into a global burden given its high incidence. There is a clinical need to create better diagnostic and therapeutic approaches to UC., Results: We fabricated P-selectin binding peptide-decorated poly lactic-co-glycolic acid (PBP-PLGA-NP) doped with two lipophilic dyes, DiL and DiD. Meanwhile, two low-toxic anti-inflammatory natural products (betulinic acid [BA] and resveratrol [Res]) were co-loaded in the PBP-PLGA-NP system. The BA/Res-loaded NPs had an average size of around 164.18 nm with a negative zeta potential (- 25.46 mV). Entrapment efficiencies of BA and Res were 74.54% and 52.33%, respectively, and presented a sustained drug release profile. Further, the resulting PBP-PLGA-NP could be internalized by RAW 264.7 cells and Colon-26 cells efficiently in vitro and preferentially localized to the inflamed colon. When intravenously injected with luminol, MPO-dependent bioluminescence imaging to visualize tissue inflammation was activated by the bioluminescence and fluorescence resonance energy transfer (BRET-FRET) effect. Importantly, injected NPs could remarkably alleviate UC symptoms yet maintain intestinal microbiota homeostasis without inducing organ injuries in the mice models of colitis., Conclusions: This theranostic nano-platform not only serves as a therapeutic system for UC but also as a non-invasive and highly-sensitive approach for accurately visualizing inflammation., (© 2022. The Author(s).)

Controllable self-assembly of photonic molecules for precise biomedicine is highly desirable but challenging to prepare multifunctional nano-phototheranostics. Herein, we developed a generic self-assembly approach to design nano-phototheranostics that provides NIR-II fluorescence imaging and phototherapy. We first designed and synthesized two amphiphilic photonic molecules, PEG 2000 -IR806 and BODIPY. Then, we prepared the co-self-assembled phototheranostic agents, PEG 2000 -IR806/BODIPY nanoparticles (PIBY NPs). The morphology of the PIBY NPs is controllable by adjusting the ratio of PEG 2000 -IR806 and BODIPY during self-assembly. The NIR-II fluorescence properties and phototherapy capability of the PIBY NPs were demonstrated in vitro and in vivo. By tuning the ratio of PEG 2000 -IR806 and BODIPY, the PIBY NPs showed various morphologies (e.g. spherical nanoparticles, nanovesicles and rod-like nanoparticles). The PEG 2000 -IR806 plays two roles in the co-self-assemblies, one is second near-infrared (NIR-II, 1000-1700 nm) agent, the other is the surfactant for BODIPY encapsulation. The phototherapeutic PIBY NPs all show bright NIR-II fluorescence and effective phototherapeutic (photothermal and photodynamic) properties, which are attributed to IR806 and BODIPY, respectively. The driving force of the self-assembly can be attributed to the electrostatic interaction between NIR806 and BODIPY and their hydrophobicity. The rod-like PIBY NPs (rPIBY NPs) demonstrated a low half inhibitory concentration (IC 50 ) of 3.96 µg/mL on U87MG cells. The NIR-II imaging showed the accumulation of rPIBY NPs in the tumor region. After systemic injection of rPIBY NPs at low dose (0.5 mg/kg), the tumor growth was greatly inhibited upon laser irradiation without noticeable side effects. This study provides a generic self-assembly approach to fabricate NIR-II imaging and phototherapeutic platform for cancer phototheranostics. STATEMENT OF SIGNIFICANCE: Nanophototheranostics providing NIR-II fluorescence imaging and phototherapy are expected to play a critical role in modern precision medicine. Controllable self-assembly of optical molecules for the fabrication of efficient nanophototheranostics is highly desirable but challenging. This work reports for the first time the co-assembly of a NIR-II imaging contrast agent and a phototherapeutic agent to yield nanophototheranostics with various morphologies. The design of molecular co-assembly with complementary optical functions can be a generic method for future the development of phototheranostics., Competing Interests: Declaration of Competing Interest The authors have no known conflicts of interests with anyone related to this manuscript submission., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of unknown etiology affecting the colon and rectum. Previous studies have found that reactive oxygen species (ROS) overproduction and transmembrane glycoprotein CD98 (encoded by SLC3A2 ) upregulation played important roles in the initiation and progression of UC. On the basis of this, a biomimetic pH-responsive metal organic framework (MOF) carrier was constructed to deliver carbon nanodot-SOD nanozyme and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) system for site-specific treatment of UC. In this system, carbon nanodots (C-dots) and CD98 CRISPR/Cas9 plasmid were successfully encapsulated into MOF carrier (ZIF-8 nanoparticles) by a one-pot approach (formed as CCZ), and then camouflaged with macrophage membrane (formed as CCZM). It was worth noting that the C-dot nanozyme showed excellent superoxide dismutase (SOD) enzymatic activity, which could scavenge ROS effectively. As expected, this biomimetic system exhibited pH-responsive, immune escape, and inflammation targeting capability simultaneously. In vitro experiments showed that ROS was significantly eliminated, and CD98 was downregulated by CCZM. In the dextran sulfate sodium salt (DSS)-induced UC model, administration of CCZM significantly ameliorated the inflammation symptoms of mice, including the colon length and pathological parameters such as epithelium integrity and inflammation infiltration. In addition, both in vitro and in vivo results demonstrated that biomimetic nanoparticles effectively reduced the expression of pro-inflammatory cytokines. Overall, this study would provide a promising approach for the precise treatment of UC.

Cardiovascular disease caused by atherosclerosis is a leading cause of morbidity and mortality worldwide. Owing to the synergistic regulation of cholesterol metabolism and lesion inflammation, the simultaneous administration of statins and nucleic acids is expected to alleviate atherosclerosis. In this work, we prepared atorvastatin- and galactose-modified trimethyl chitosan nanoparticles (GTANPs) with dual targeting to hepatocytes and lesional macrophages for encapsulating Baf60a siRNA (siBaf60a) and anti-miR-33 pDNA (pAnti-miR-33), attaining the effective codelivery of statins and nucleic acids. We demonstrated that GTANPs/siBaf60a and GTANPs/pAnti-miR-33 had in vitro antiinflammatory and lipid regulating efficacy. In ApoE-knockout atherosclerotic mice, intravenously injected GTANPs/siBaf60a synergistically reduced the plasma cholesterol and atherosclerotic plaque area; more importantly, orally delivered GTANPs/pAnti-miR-33 synergistically increased the levels of plasma high-density lipoprotein cholesterol (HDL-C) and antiinflammatory cytokines, resulting in a satisfactory antiatherosclerotic outcome. Our results suggest that codelivery of statins and nucleic acids provides a promising strategy for the treatment of atherosclerosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Activating CD8 + T cells by antigen cross-presentation is remarkably effective at eliminating tumours. Although this function is traditionally attributed to dendritic cells, tumour-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumour-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8 + T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbour hyperactive cysteine protease activity in their lysosomes, which impedes antigen cross-presentation, thereby preventing CD8 + T cell activation. We developed a DNA nanodevice (E64-DNA) that targets the lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases that is present specifically inside the lysosomes of TAMs, improves their ability to cross-present antigens and attenuates tumour growth via CD8 + T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumour regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The treatment efficiency of the Fenton reaction is expected to be greatly restricted due to problems such as inefficient delivery of Fenton catalysis, limited H 2 O 2 concentration and uneven tumour tissue. Accurate photothermal therapy (PTT) could improve the efficiency of Fenton catalysis to some extent by raising the temperature. However, the heat shock response (HSR) of tumour cells caused by PTT and Fenton reaction would attenuate the treatment effect. In this study, we developed an iron ions-mediated Fenton reaction combined with a PTT treatment platform based on a metal-organic framework, i.e. , PPy-CTD@MIL-100@MPCM nanoparticles (PCMM NPs), and further explored the inhibitory effect of PCMM NPs on the heat shock response (HSR). PCMM NPs could accumulate in tumour tissue via the coated macrophage cell membranes (MPCMs) to target inflammatory tissues. The photothermal effect of polypyrrole (PPy) accelerated the release of cantharidin (CTD) and iron ions loaded in the PCMM NPs. CTD, as an HSR inhibitor, could inhibit this response of tumour cells and improve the effect of PTT. Meanwhile, the heat generated during the PTT process could improve the efficiency of the Fenton reaction. This study suggested that PCMM NPs could serve as a combined treatment platform to enhance the Fenton reaction based on amplified photothermal therapy.

Background: Breast cancer is the most prevalent cancer among women. Doxorubicin (DOX) is a common chemotherapeutic drug used to treat many different cancers. However, multidrug resistance limits the treatment of breast cancer. MDR1 siRNA (siMDR1) combinatorial therapy has attracted significant attention as a breakthrough therapy for multidrug resistance in tumors. However, naked siRNA is easily degraded by enzymatic hydrolysis requiring an siRNA carrier for its protection. Human serum albumin (HSA) was selected as the carrier due to its excellent biocompatibility, non-toxicity, and non-immunogenicity. Cetuximab was used to modify the HSA nanoparticles in order to target the tumor tissues., Methods: This study used a central composite design response surface methodology (CCD-RSM) to investigate the optimal formula for HSA NPs preparation. Cex-HSA/DOX/MDR1 siRNA (C-H/D/M) was characterized by dynamic light scattering and transmission electron microscopy. The efficacy of C-H/D/M tumor growth inhibitory activity was investigated in vitro and in vivo using confocal imaging, MTT assay, and an MCF-7/ADR tumor-bearing mice model. RT-qPCR, ELISA analysis, and flow cytometry were used to investigate the in vitro antitumor mechanisms of C-H/D/M., Results: The diameter and PDI of the C-H/D/M were 173.57 ± 1.30 nm and 0.027 ± 0.004, respectively. C-H/D/M promoted and maintained the sustained release and the uptake of DOX significantly. After transfection, the MDR1 mRNA and P-gp expression levels were down-regulated by 44.31 ± 3.6% (P < 0.01) and 38.08 ± 2.4% (P < 0.01) in an MCF-7/ADR cell line. The fluorescent images of the treated BALB/c nude mice revealed that C-H/D/M achieved targeted delivery of siMDR1 and DOX into the tumor tissue. The in vivo tumor inhibition results demonstrated that the tumor inhibition rate of the C-H/D/M treated group was 54.05% ± 1.25%. The biosafety results indicated that C-H/D/M did not induce significant damages to the main organs in vivo., Conclusion: C-H/D/M can be used as an ideal non-viral tumor-targeting vector to overcome MDR and enhance the antitumor effect., Competing Interests: The authors declare no conflict of interest., (© 2021 Yang et al.)

To achieve the co-delivery of chemotherapeutic drugs, genes, and immune agents in a single nanoparticulate system, p-mercaptobenzoic acid-grafted N, N, N-trimethyl chitosan nanoparticles (MT NPs) were successfully synthesized. Paclitaxel (PTX) was encapsulated into the hydrophobic core of the MT NPs, and meanwhile, survivin shRNA-expressing plasmid (iSur-pDNA) and recombinant human interleukin-2 (rhIL-2) were loaded onto the hydrophilic shell of the MT NPs. Owing to the redox-sensitiveness of MT NPs, a rapid release of PTX was triggered by the high concentration of glutathione. The synergistic effects of PTX (1.5 mg/kg), iSur-pDNA (1.875 mg/kg), and rhIL-2 (6 × 10 5  IU/kg) at a low dose endowed the MT/PTX/pDNA/rhIL-2 NPs with enhanced antitumor efficacies and improved tumor-induced immunosuppression. These results demonstrated that the co-delivery of PTX, iSur-pDNA, and rhIL-2 by the amphiphilic chitosan based NPs with redox-sensitiveness could be a promising strategy in the treatment of tumors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

CRISPR/Cas9 system has been used as the most powerful gene editing tool for precision medicine and advanced gene therapy. However, its wide applications are limited by the poor biosafety of lentivirus delivery vectors though with high-efficiency transduction. To construct a safer vector and promote genome integration, the CRISPR/Cas9 gene is cloned into a plasmid-based non-viral safe vector Sleeping-Beauty (SB) transposon in this study to obtain pT2SpCas9. Meanwhile, PDA/DEX-PEI@HA (PDPH) nanoparticles are constructed to facilitate the precise CRISPR/Cas9 targeting delivery, by using polydopamine (PDA) as the carrier, hyaluronic acid (HA) as the cell-targeting ligand and dexamethasone (DEX) as the nuclear localization signal (NLS). The results showed that PDPH could deliver pDNA efficiently into the cell and further into the nucleus. The transfection efficiency of PDPH is much higher than that of NPs without HA and DEX. Remarkably, the cytotoxicity of PDPH is negligible in comparison to PEI 25k and PEI 10k . Western blots showed that after the transfection of PDPH/pT2SpCas9-Nanog/SB11, Nanog protein in HeLa cells is knocked out, and the proliferation and migration abilities of tumor cells are significantly decreased. This study demonstrates that PDA/DEX-PEI 25k @HA/pT2SpCas9 (PDPH 25 K /pT2SpCas9) has the great potential as a non-viral gene vector for CRISPR/Cas9 delivery and clinical medication., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The validity and biocompatibility of irrigating agents are imperative for the success of root canal therapy. The imperfections in the currently available irrigants highlight the fact that more advanced technologies and strategies are required for complete disinfection in endodontic treatments. In the present study, a Fenton reaction-enhanced antimicrobial sonodynamic therapy (SDT) platform was fabricated for root canal disinfection. Firstly, mesoporous silica nanoparticles (MSNs) were synthesized, grafted with an amino group and then conjugated with sonosensitizer protoporphyrin IX (PpIX). Iron ions were then anchored (M@P-Fe) to initiate a Fenton reaction. Nanoparticle characterization by size and zeta potential measurements, scanning electron microscopy, transmission electron microscopy and thermogravimetric analysis confirmed that the platform was successfully developed. Reactive oxygen species (ROS) generation assessment, methylene blue degradation and electron spin resonance assays illustrated upon ultrasound (US) irradiation, that augmented ROS, can be produced by US activated PpIX and iron mediated Fenton reactions from low concentration H 2 O 2 (0.01%). In vitro anti- Enterococcus faecalis efficacy was demonstrated by growth curve and colony forming unit measurements. Confocal laser scanning microscopy and scanning electron microscopy observations illustrated the effectiveness of the platform on in situ biofilm eradication in root canal. Owing to the stronger oxidizing capability and short lifetime of ROS, the Fenton reaction-enhanced SDT can induce detrimental oxidative damage to bacteria upon activation of US while avoiding nonspecific toxicity to cells, which was verified by cytotoxicity evaluations using CCK-8 assay and morphology observation of MC3T3-E1 cells. Compared to commonly used NaClO, this nanoplatform displayed desirable anti-bacterial, anti-biofilm abilities and better biocompatibility. These results highlight that the integrated M@P-Fe + US + H 2 O 2 platform is a promising candidate for US enhanced root canal irrigation and disinfection.

Nano graphene oxide (NGO) has high drug-loading capacity due to its huge surface area. However, the limited stability and the poor biocompatibility of NGO hampered its application as drug delivery carrier under physiological conditions. Thereby, a new strategy of using chemical conjugation on NGO with hydrophilic polymers was adopted but currently was too complicated, low yield and costly. In this study, doxorubicin-hyd-PEG-folic acid (DOX-hyd-PEG-FA) polymers were coated on the surface of NGO via π-π stocking and the hydrophobic effect between DOX and NGO. With the PEG shell protection, the biocompatibility of NGO was significantly improved. The drug-loading capacity of nanoparticles was more than 100%. FA ligands on the nanoparticle could guide the nanoparticles actively targeting to tumour cells. The hydrazone bond between DOX and PEG was decomposed spontaneously in the weakly acidic environment, which made PEG layer dissociated from NGO. Furthermore, DOX was easily protonized at low pH conditions, which weakened the interaction between DOX and NGO. Thus, DOX could be released rapidly from the nanoparticles in tumour cells. In summary, NGO@DOX-hyd-PEG-FA is an easy-prepared nanoparticle with excellent biocompatibility, high pH-sensitivity and active tumour targeting. Therefore, it is a promising multifunctional nanocarrier effective for targeted drug delivery.

Developing novel photosensitizers for deep tissue imaging and efficient photodynamic therapy (PDT) remains a challenge because of the poor water solubility, low reactive oxygen species (ROS) generation efficiency, serve dark cytotoxicity, and weak absorption in the NIR region of conventional photosensitizers. Herein, cyclometalated iridium (III) complexes (Ir) with aggregation-induced emission (AIE) feature, high photoinduced ROS generation efficiency, two-photon excitation, and mitochondria-targeting capability were designed and further encapsulated into biocompatible nanoparticles (NPs). The Ir-NPs can be used to disturb redox homeostasis in vitro, result in mitochondrial dysfunction and cell apoptosis. Importantly, in vivo experiments demonstrated that the Ir-NPs presented obviously tumor-targeting ability, excellent antitumor effect, and low systematic dark-toxicity. Moreover, the Ir-NPs could serve as a two-photon imaging agent for deep tissue bioimaging with a penetration depth of up to 300 μm. This work presents a promising strategy for designing a clinical application of multifunctional Ir-NPs toward bioimaging and PDT., (© 2021. The Author(s).)

Background: Pesticide residue and its poor utilization remains problematic in agricultural development. To address the issue, a nano-pesticide has been developed by incorporating pesticide acetamiprid in porous silica nanoparticles., Results: This nano-pesticide had an acetamiprid loading content of 354.01 mg g -1 . Testing LC 50 value against tea aphids of the commercial preparation was three times that of the nano-pesticide. In tea seedlings (Camellia sinensis L.), acetamiprid was transported upward from the stem to the young leaves. On day 30, the average retained concentrations in tea leaves treated with the commercial preparation were about 1.3 times of that in the nano-pesticide preparation. The residual concentrations of dimethyl-acetamiprid in leaves for plants treated with the commercial preparation were about 1.1 times of that in the nano-pesticide preparation. Untargeted metabolomics of by LC-MS on the young leaves of tea seedlings under nano-pesticide and commercial pesticide treatments showed significant numbers of differentially expressed metabolites (P < 0.05 and VIP > 1). Between the nano-pesticide treatment group and the commercial preparation treatment group there were 196 differentially expressed metabolites 2 h after treatment, 200 (7 th day), 207 (21 st day), and 201 (30 th day) in negative ion mode, and 294 (2 nd h), 356 (7 th day), and 286 (30 th day) in positive ion mode. Preliminary identification showed that the major differentially expressed metabolites were glutamic acid, salicylic acid, p-coumaric acid, ribonic acid, glutamine, naringenin diglucoside, sanguiin H4, PG (34:2) and epiafzelechin., Conclusions: This work demonstrated that our nano-pesticide outperformed the conventional pesticide acetamiprid in terms of insecticidal activity and pesticide residue, and the absorption, transportation and metabolism of nano-pesticide in tea plant were different, which pave a new pathway for pest control in agricultural sector., (© 2021. The Author(s).)

In situ synthesis of DNA origami structures in living systems is highly desirable due to its potential in biological applications, which nevertheless is hampered by the requirement of thermal activation procedures. Here, we report a photothermal DNA origami assembly method in near-physiological environments. We find that the use of copper sulfide nanoparticles (CuS NPs) can mediate efficient near-infrared (NIR) photothermal conversion to remotely control the solution temperature. Under a 4 min NIR illumination and subsequent natural cooling, rapid and high-yield (>80%) assembly of various types of DNA origami nanostructures is achieved as revealed by atomic force microscopy and single-molecule fluorescence resonance energy transfer analysis. We further demonstrate the in situ assembly of DNA origami with high location precision in cell lysates and in cell culture environments.

B lymphoblastic leukemia (B-LL) is a clonal hematopoietic stem cell neoplasm derived from B-cell progenitors, which mainly occurs in children and adolescents and is one of the main causes of death from malignant tumors in this population. The surface marker CD19 is specifically expressed on the membrane of most malignant B-cells, which is widely used as a marker of B-LL antigen-specific immunotherapy. In this study, mesoporous titanium dioxide nanoparticles (MTNs)-based antibody drug delivery system was designed for B-LL treatment. Anti-CD19 monoclonal antibody was conjugated to PEGylated MTNs, and doxorubicin (DOX) was loaded in the nanoparticle. The CD19-PEG-MTN/DOX nanoparticle could recognize CD19 + B-LL cell lines and induced them apoptosis, but nontoxic for the normal cells. Further, after treated with CD19-PEG-MTN/DOX nanoparticle, pro-apoptotic proteins Bax and Caspase-3 in KOPN 8 and NALM-6 cells were significantly upregulated, but anti-apoptotic proteins Bcl2, MCL-1, HSP 70, and BAG 3 were downregulated, which indicated the activation of the apoptosis pathway by the nanodrug. By contrast, CD19-PEG-MTN/DOX didn't play a part on CD19 - cell line U937. Besides, the cytotoxicity of CD19-PEG-MTN/DOX was low with good biocompatibility. Collectively, CD19-PEG-MTN/DOX is a promising antitumor nanodrug for the treatment of B-LL., Competing Interests: Conflicts of interest There are no conflicts of interest to declare., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Cytosolic delivery of small interfering RNA (siRNA) remains challenging, and a profound understanding of the cellular uptake and intracellular processing of siRNA delivery systems could greatly improve the development of siRNA-based therapeutics. Here, we show that caveolae-mediated endocytosis (CvME) accounts for the robust siRNA delivery of mannose-modified trimethyl chitosan-cysteine/tripolyphosphate nanoparticles (MTC/TPP NPs) to macrophages by circumventing lysosomes. We show that the Golgi complex and ER are key organelles required for the efficient delivery of siRNA to macrophages in which the siRNA accumulation positively correlates with its silencing efficiency ( r = 0.94). We also identify syntaxin6 and Niemann-Pick type C1 (NPC1) as indispensable regulators for MTC/TPP NPs-delivered siRNA into macrophages both in vitro and in vivo . Syntaxin6 and NPC1 knockout substantially decrease the cellular uptake and gene silencing of the siRNA delivered in MTC/TPP NPs in macrophages, which result in poor therapeutic outcomes for mice bearing acute hepatic injury. Our results suggest that highly efficient siRNA delivery can be achieved via CvME, which would give ideas for designing optimal delivery vectors to facilitate the clinical translation of siRNA drugs.

Background: siRNA brings hope for cancer therapy. However, there are many obstacles for application of siRNA in clinical. Because of the excellent biocompatibility, non-toxicity and non-immunogenicity of bovine serum albumin (BSA), BSA-based nanoparticles have been widely designed as a drug carrier system., Methods: The optimal formula for BSA NPs preparation was investigated by central composite design response surface methodology (CCD-RSM), BSA-based survivin-siRNA delivery system (BSA NPs/siRNA) was characterized by dynamic light scattering, atomic force microscope, transmission electron microscope and Bradford method. The in vitro anti-tumor effect and mechanism of BSA NPs were investigated by confocal microscopic imaging, MTT assay, RT-qPCR and ELISA analysis. Moreover, the anti-tumor effect, distribution and biosafety of BSA NPs were studied in vivo., Results: The optimal formula for BSA NPs was settled to be 20 mg/mL for BSA concentration, 9 for pH value, 136% for crosslinking degree and 1.6 mL/min for speed of ethanol addition. BSA NPs/siRNA could remain stable at 4°C for 4 weeks and protect siRNA from degradation by RNase A. Besides, BSA NPs/siRNA could maintain a sustained release of siRNA and promote the uptake of siRNA significantly. The survivin-mRNA level and the survivin-protein level were decreased by 55% ± 1.6% and 54% ± 1.6% separately. The in vivo tumor inhibition results suggested that the tumor inhibition rate of BSA NPs/siRNA-treated group was 54% ± 12% and was similar with that of DOX-treated group (57% ± 9.2%, P > 0.05). The biosafety results confirmed that BSA NPs/siRNA could not induce significant damages to the main organs and blood in vivo., Conclusion: These results demonstrated that CCD-RSM was an effective tool for preparation analysis, and the BSA NPs/siRNA was a promising system for siRNA-based gene therapy., Competing Interests: The authors declare no conflicts of interest., (© 2021 Wang et al.)

Accurate diagnosis and efficient treatment of tumors are highly significant in battling cancer. Near-infrared II (NIR-II) fluorescence imaging shows big promise for deep tumor visualization in living systems due to high temporal and spatial resolution and deep tissue penetration capability, whereas the development of efficient NIR-II probes for tumor theranostics still faces a huge challenge. Herein, we have designed and constructed intelligent mPEG 5000 -PCL 3000 -encapsulated NIR-II nanoprobe ZM1068-NPs that showed great chemical stability and excellent biocompatibility. With the merits of the strong fluorescence in the NIR-II region and prominent optical-thermal conversion efficiency, this probe was successfully used for NIR-II imaging-guided surgery and photothermal therapy of breast carcinoma in living mice. More notably, it was for the first time found that ZM1068 dyes could be covalently on-site-immobilized within tumors through the thiol-chlor nucleophilic substitution reaction, resulting in improved tumor accumulation and retention time. We thus envision that this probe may provide an attractive means for precise cancer diagnosis and treatment.

Single chemotherapy often causes severe adverse effects and drug resistance to limit therapeutic efficacy. As a noninvasive approach, photothermal therapy (PTT) represents an attractive option for cancer therapy due to the benefits of remote control and precise treatment methods. Nanomedicines constructed with combined chemo-photothermal properties may exert synergistic effects and improved antitumor efficacy. In this study, we developed polydopamine (PDA)-coated nanoparticles grafted with folic acid (FA) and polyethylene glycol to transport doxorubicin (DOX) for targeted cancer therapy. The results showed that this delivery vehicle has a nanoscale particle size and narrow size distribution. No particle aggregation or significant drug leakage was observed during the stability test. This system presented excellent photothermal conversion capability under near-infrared light (NIR) laser irradiation due to the PDA layer covering. In vitro dissolution profiles demonstrated that sequential and triggered DOX release from nanoparticles was pH-, NIR irradiation-, and redox level-dependent and could be best fitted with the Ritger-Peppas equation. FA modification effectively promoted the intracellular uptake of nanoparticles by HepG2 cells and therefore significantly inhibited cell recovery and induced tumor cell apoptosis. Compared to the free DOX group, nanoparticles reduced the DOX concentration in the heart to avoid drug-related cardiotoxicity. More importantly, the in vivo antitumor efficacy results showed that compared with the single chemotherapy strategy, the nanoparticle group exerted combined and satisfactory tumor growth inhibition effects with good biocompatibility. In summary, this nanocarrier delivery system can organically combine chemotherapy and PTT to achieve effective and precise cancer treatment.

Photodynamic therapy (PDT) is a promising therapy due to its efficiency and accuracy. The photosensitizer is delivered to the target lesion and locally activated. Viral nanoparticles (VNPs) have been explored as delivery vehicles for PDT in recent years because of their favorable properties, including simple manufacture and good safety profile. They have great potential as drug delivery carriers in medicine. Here, we review the development of PDT photosensitizers and discuss applications of VNP-mediated photodynamic therapies and the performance of VNPs in the treatment of tumor cells and antimicrobial therapy. Furthermore, future perspectives are discussed for further developing novel viral nanocarriers or improving existing viral vectors.

Prussian blue nanoparticles (PBNPs) have attracted increasing research interest in immunosensors, bioimaging, drug delivery, and application as therapeutic agents due to their large internal pore volume, tunable size, easy synthesis and surface modification, good thermal stability, and favorable biocompatibility. This review first outlines the effect of tumor markers using PBNPs-based immunosensors which have a sandwich-type architecture and competitive-type structure. Metal ion doped PBNPs which were used as T 1 -weight magnetic resonance and photoacoustic imaging agents to improve image quality and surface modified PBNPs which were used as drug carriers to decrease side effects via passive or active targeting to tumor sites are also summarized. Moreover, the PBNPs with high photothermal efficiency and excellent catalase-like activity were promising for photothermal therapy and O 2 self-supplied photodynamic therapy of tumors. Hence, PBNPs-based multimodal imaging-guided combinational tumor therapies (such as chemo, photothermal, and photodynamic therapies) were finally reviewed. This review aims to inspire broad interest in the rational design and application of PBNPs for detecting and treating tumors in clinical research.

Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.

Foliar absorption of zinc (Zn) is limited by several barriers, the first of which is the leaf cuticle. In this study, we investigated the absorption of Zn from Zn oxide nanoparticles (ZnO-NPs) in wheat (Triticum aestivum cv Gladius) and sunflower (Helianthus annuus cv Hyoleic 41) to determine the importance of NP surface coating for Zn absorption. Fourier transform infrared (FTIR) spectroscopy showed a higher polysaccharide content in the wheat cuticle than sunflower, indicated by a more pronounced glycosidic bond at 1020 cm -1 , but wax and cutin content were similar. Scanning electron microscopy (SEM) revealed that trichome density was twice as high in wheat (3600 ± 900 cm -2 ) as in sunflower (1600 cm -2 ) and stomatal density four times higher in sunflower (6400 ± 800 cm -2 in wheat and 22 900 cm -2 in sunflower). Suspensions of ZnO-NPs with coatings of different hydrophobicity were applied to leaves to compare Zn absorption using X-ray fluorescence microscopy (XFM) and inductively coupled plasma mass spectroscopy (ICP-MS). Absorption of Zn was similar between wheat and sunflower when Zn was applied at 1000 mg Zn l -1 , but much less Zn was absorbed from all ZnO products than from soluble Zn fertiliser. Particle coating did not affect Zn absorption, but it may facilitate particle adhesion to leaves, providing a longer-term source of resupply of Zn ions to the leaves. Differences in leaf surface characteristics did not affect Zn absorption, indicating that the cuticle is the main pathway of absorption under these conditions., (© 2020 Scandinavian Plant Physiology Society.)

Antimicrobial peptide PA-C1b (chensinin-1b conjugated with palmitic acid) showed potent anticancer activity with no obvious hemolytic activity, which made it a potential agent for treating cancers. However, after in vivo administration, peptides can be degraded by proteases because there is no effective protection. In this study, a tumor-targeting photoresponsive antimicrobial peptide delivery system was developed, and the peptide PA-C1b labeled with the dye sulfo-cyanine7 (Cy7) was loaded into mesoporous silica nanoparticles (MSNs). The final MSN@Cy7-PA-C1b nanoparticles were wrapped by graphene oxide (GO), and then folic acid was conjugated to the surface of the MSNs for targeting purposes. The final MSN@Cy7-PA-C1b@FA-GO nanoparticles were constructed to allow light-mediated peptide release and folate receptor-targeted cancer therapy. The Cy7 dye serves as a real-time indicator, and GO acts as a gatekeeper to prevent leakage of the loaded peptides in the absence of near-infrared light irradiation. Upon light irradiation, the GO wrapping detaches, and the photoresponsive peptide delivery system works well both in in vitro cell experiments and during in vivo administration in mouse tumor experiments. The construction of the MSN@Cy7-PA-C1b@FA-GO platform provides a novel approach to deliver antimicrobial peptides in vivo for the treatment of infections by pathogenic microorganisms and cancers., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The combination of radiotherapy and chemotherapy is a common and useful treatment mode for tumours. But traditional methods inevitably lead to a variety of side effects. A drug delivery system (DDS), which has good biocompatibility and strong anti-tumour ability, is expected to solve this problem. Studies have shown that Ce-based nanoparticles (NPs) have good radiosensitization effect through the photoelectric effect. Hence, cisplatin-loaded LiLuF₄ :Ce 3+ scintillation NPs (NP + Cis) were first constructed in this study, which was synthesized by the crystal precipitation method and characterized by transmission electron microscopy (TEM). Subsequently, its toxicity was verified, and the radiosensitization effect and basic radiosensitization mechanism on tumour cells and tumour-bearing mice were researched. Results showed that NP + Cis triggered massive DNA damage and effectively inhibited cell viability in vitro under the exposure of X-ray irradiation (IR). Moreover, the experiments in vivo showed that the NP + Cis had higher biosafety, which could absorb enough irradiation and produce a synergistic inhibitory effect on tumours through the releasing of Cis. NP + Cis can improve the performance of DDS in chemoradiotherapy.

Silver (Ag) is released from a range of products and accumulates in agricultural soils as silver sulfide (Ag 2 S) through the application of Ag-containing biosolids as a soil amendment. Although Ag 2 S is comparatively stable, its solubility increases with salinity, potentially altering its impacts on microbial communities due to the anti-microbial properties of Ag. In this study, we investigated the impacts of Ag on the microbially mediated N cycle in saline soils by examining the relationship between the (bio)availability of Ag 2 S and microbial functioning following the application of Ag 2 S-containing sludge. Synchrotron-based X-ray absorption spectroscopy (XAS) revealed that the Ag 2 S was stable within the soil, although extractable Ag concentrations increased up to 18-fold in soils with higher salinity. However, the extractable Ag accounted for <0.05% of the total Ag in all soils and had no impact on plant biomass or soil bacterial biomass. Interestingly, at high soil salinity, Ag 2 S significantly increased cumulative N 2 O emissions from 80.9 to 229.2 mg kg -1 dry soil (by 180%) compared to the corresponding control sludge treatment, which was ascribed to the increased abundance of nitrification and denitrification-related genes (amoA, nxrB, narG, napA, nirS, and nosZ) and increased relative abundance of denitrifiers (Rhodanobacter, Salinimicrobium, and Zunongwangia). Together, our findings show that the application of Ag 2 S-containing sludge to a saline soil can disrupt the N cycle and increase N 2 O emissions from agroecosystems., 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 © 2020 Elsevier Ltd. All rights reserved.)

The iron and nickel bimetallic nanoparticles supported by the block copolymer polystyrene-block-poly (acrylic acid) (PS-b-PAA-nZVI-Ni) were synthesized successfully and were applied to assess the degradation of 1,1,1-trichloroethane (1,1,1-TCA) in water. An optimal dose of Ni loading was 2 wt%, while an optimal mass ratio of PS-b-PAA to Ni/Fe, i.e., 0.5:1, at which the dechlorination efficiency was a maximum. The size of PS-b-PAA-nZVI-Ni nanoparticles (average size ~ 50 nm) was three times smaller than that of nZVI-Ni due to the prevention of agglomeration of the resultant zerovalent iron nanoparticles by PS-b-PAA. In the applying aspect, the pseudo-first-order rate constant (K obs ) of 1,1,1-TCA removal by PS-b-PAA-nZVI-Ni was 0.0142 min -1 within 240 min, which was approximately five times higher than nZVI. Meanwhile, PS-b-PAA-supported nZVI-Ni nanoparticles penetrated much deeper in quartz sand columns than nZVI-Ni nanoparticles, indicating PS-b-PAA had significant influence on nZVI transport. The findings from this study suggested that PS-b-PAA-nZVI-Ni, with its high reactivity, selective screening for 1,1,1-TCA, could be one significant potential for use as remedial agent to treat chlorinated solvents in water.

Poly γ-glutamic acid (γ-PGA) is attractive due to its desirable biological properties such as nontoxicity, excellent biocompatibility, and minimal immunogenicity. Additionally, γ-PGA could be recognized by γ-glutamyl transpeptidase, which is regarded as a potential biomarker for many tumors. In this study, we have developed a new biodegradable, reduction sensitive, and tumor-specific gene nano-delivery platform consisting of a cationic carrier (SSBPEI) for siRNA condensation, mPEG shell for nanoparticle stabilization, and γ-PGA for accelerated cellular uptake. Disulfide bonds (-SS-) could be reduced specifically in the tumor environment, which is full of reductants such as glutathione reductase. Conjugating polyethylene glycol (PEG) to the γ-PGA led to the formation of mPEG-g-γ-PGA, with a decreased positive charge on the surface of SSBPEI@siRNA and substantially higher stability in an aqueous medium. As a result, mPEG-g-γ-PGA/SSBPEI@siRNA nanoparticles could protect siRNAs from RNase A degradation and release siRNAs in a reduction sensitive way. The multifunctional delivery system was shown to silence the Survivin gene and further promote chemotherapeutic drug-induced apoptosis in the A549 NSCLC cell line efficiently, thereby representing a novel promising platform for the delivery of siRNAs., 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 © 2020 Elsevier B.V. All rights reserved.)

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based β-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with β-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd 0 nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing β-d-glucose oxidation to form hydrogen peroxide (H 2 O 2 ) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.

The heat shock response (HSR) induced by photothermal therapy (PTT), which can cause tumor cells to resist apoptosis, has increasingly attracted the attention of researchers. Synergistic treatment of tumors using multiple means to improve therapeutic efficiency would be a promising strategy for effective cancer treatment. In this study, a cancer cell membrane-camouflaged nanocarrier was developed and loaded with tellurium (Te) and cantharidin (CTD) for efficient combinatorial therapy. The designed nanoparticles (m-CTD@Te) used a 4T1 cell membrane coating as the shell with homologous targeting capability, CTD as an the HSR inhibitor and antitumor drug, and Te as a PTT and photodynamic therapy (PDT) photosensitizer. An in vivo study indicated that the tumor inhibition rate of this combinatorial therapy could reach approximately 82.3% in 4T1 mammary tumor models. This study suggested that m-CTD@Te, as a versatile biomimetic nanoplatform, provides a new alternative for more precise and effective tumor treatment. STATEMENT OF SIGNIFICANCE: In this work, we constructed cell membrane-coated biomimetic nanoparticles (m-CTD@Te) to suppress cancer effectively through synergistic treatment. The developed m-CTD@Te nanoparticles presented strong homologous targeting capabilities. The encapsulated Te triggered PDT and PPT under the near-infrared laser irradiation. Subsequently, the PTT triggered the release of CTD, which could suppress the HSR of tumor and achieve chemotherapy. In addition, due to the presence of outer cell membrane coating, these m-CTD@Te nanoparticles showed good biocompatibility to healthy cells., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Stimuli-responsive biomaterials that contain logic gates hold great potential for detecting and responding to pathological markers as part of clinical therapies. However, a major barrier is the lack of a generalized system that can be used to easily assemble different ligand-responsive units to form programmable nanodevices for advanced biocomputation. Here we develop a programmable polymer library by including responsive units in building blocks with similar structure and reactivity. Using these polymers, we have developed a series of smart nanocarriers with hierarchical structures containing logic gates linked to self-immolative motifs. Designed with disease biomarkers as inputs, our logic devices showed site-specific release of multiple therapeutics (including kinase inhibitors, drugs and short interfering RNA) in vitro and in vivo. We expect that this 'plug and play' platform will be expanded towards smart biomaterial engineering for therapeutic delivery, precision medicine, tissue engineering and stem cell therapy.

Despite many efforts in the rational design of nanoparticles (NPs) to overcome the biological barriers to small interfering RNA (siRNA) delivery for improving gene silencing efficiency, little is known about the correlations between siRNA release kinetics and RNA interference (RNAi) efficiency and inflammation therapy via oral delivery. On the basis of mannose-modified trimethyl chitosan-cysteine (MTC) polymers, seven types of MTC NPs containing tumor necrosis factor (TNF)-α siRNA were prepared through ionic gelation. The siRNA release kinetics from MTC NPs were finely tuned by adjusting the kinds and amounts of the crosslinkers involved. These MTC NPs exhibited no disparities in siRNA protection against enzymatic degradation in physiological fluids and cellular uptake in macrophages; however, they showed distinct in vitro siRNA release profiles and intracellular unpacking kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for efficient, prompt, and prolonged RNAi, contributing to desired therapeutic efficacy in acute and chronic inflammatory murine models following oral delivery. However, MTC NPs insufficiently releasing siRNA could not elicit effective RNAi. Collectively, the present investigation might provide broad insights into the optimization of siRNA nanocarriers with respect to their release kinetics for improving RNAi efficacies aiming at different types of inflammatory diseases. STATEMENT OF SIGNIFICANCE: siRNA release kinetics in the cytoplasm and pathological characteristics of diseases themselves determine the therapeutic efficacy of siRNA delivery. Herein, by adjusting the kinds and amounts of the crosslinkers involved, we developed seven types of MTC NPs containing TNF-α siRNA with distinct siRNA release kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for prompt and prolonged RNAi, respectively, contributing to desired therapeutic efficacy in acute and chronic inflammation following oral delivery. These results might provide broad insights into the optimization of siRNA nanocarriers in respect to their release kinetics for improving therapeutic outcomes toward different clinical requirements., (Copyright © 2019. Published by Elsevier Ltd.)

CD47, a transmembrane protein overexpressed in most tumors, limits macrophage phagocytosis by interacting with macrophage signal-regulated protein α (SIRPα). In this study, we have developed CD47-targeted bismuth selenide nanoparticles (Ab-PEG-Bi 2 Se 3 ) that increase phagocytosis of cancer cells by macrophages to actualize improved photothermal therapy (PTT). The functionalized nanoparticles were constructed by conjugating anti-CD47 antibody (Ab) to PEGylated bismuth selenide nanoparticles (PEG-Bi 2 Se 3 ). The anti-CD47 antibody modified on the nanoparticles enhanced the phagocytic activity of macrophages toward tumor cells by specifically blocking the crosstalk between CD47 and SIRPα. Meanwhile, Ab-PEG-Bi 2 Se 3 showed excellent photothermal performance including strong near infrared (NIR) absorbance, high photothermal conversion efficiency and photostability, and exhibited outstanding in vitro PTT effect under NIR laser irradiation. In vivo therapeutic experiments revealed that this CD47-targeted PTT nanoagent, with the assistance of enhanced macrophage phagocytosis, achieved the goal of tumor eradication. Besides, toxicity studies confirmed that Ab-PEG-Bi 2 Se 3 had good biocompatibility. In conclusion, Ab-PEG-Bi 2 Se 3 may serve as an efficient PTT platform in combination with macrophage-mediated immunotherapy to improve antitumor efficacy., (Copyright © 2019 Elsevier B.V. All rights reserved.)