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Inflammatory neutrophils (INEs), motivated by cytokines, continue to migrate into the inflamed joints, driving the development of RA. Hence, inducing apoptosis of INEs to reduce recruitment at inflamed joints is an effective strategy for the treatment of RA. However, simply apoptotic INEs may trigger the release of neutrophil extracellular traps (NETs) and accelerate the inflammatory process. To overcome these drawbacks, an RGD-modified bovine serum albumin (BSA) nanoparticles (CBR NPs) was fabricated to selectively target INEs in situ for intracellular delivery of CLT. Studies have demonstrated that CBR NPs can selectively target circulating INEs and induce INEs apoptosis. Meanwhile, CBR NPs inhibited the activation of NETs via NF-κB pathway and the release of Cit-H3 thereby blocking the release process of NETs. In collagen-induced arthritis (CIA) mouse model, CBR NPs suppressed the inflammatory response, and reduced the toxic effects of CLT. In summary, this study shed light on an innovative approach to treat RA by inducing apoptosis of circulating INEs and inhibiting NETs. STATEMENT OF SIGNIFICANCE: RGD-modified bovine serum albumin (BSA) nanoparticles for delivering celastrol, abbreviated as CBR NPs, were constructed to inhibit the infiltration of circulating inflammatory neutrophils (INEs) into inflamed joints while inhibiting the release of NETs to alleviate tissue damage. CBR NPs were prepared for the first time to induce apoptosis of INEs; CBR NPs could inhibit the release of NETs while inducing apoptosis of INEs in vivo and vitro cellular experiments; CBR NPs had favorable anti-inflammatory effects and low toxicity side-effects in collagen-induced arthritis (CIA) mouse models. The application of nanotechnology to induce apoptosis of INEs while inhibiting the release of NETs was a promising approach for the treatment of RA., 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 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Circumventing immune resistance and boosting immune response is the ultimate goal of cancer immunotherapy. Herein, we reported a tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle for specifically inducing immunogenic cell death (ICD) in combination with TAM depletion. A versatile ROS-cleavable camptothecin (CPT) prodrug (DCC) was synthesized through a thioacetal linker between CPT and the ROS generator cinnamaldehyde (CA), which could self-assemble into a uniform prodrug nanoparticle to realize a positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." This DCC was further modified with the TAM membrane (abbreviated as DCC@M2), which could not only target both primary tumors and lung metastasis nodules through VCAM-1/α 4 β 1 integrin interaction but also absorb CSF-1 secreted by tumor cells to disturb the interaction between TAMs and cancer cells. Our nanodecoy could effectively induce ICD cascade and deplete TAMs for priming tumor-specific effector T cell infiltration for antitumor immune response activation, which represents a versatile approach for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle was fabricated for the first time. This ROS-cleavable camptothecin (CPT)/cinnamaldehyde (CA) prodrug (DCC) could self-assemble into a uniform nanoparticle to realize the positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." After TAM membrane coating, this system (DCC@M2) could not only target both primary tumors and lung metastatic nodules but also scavenge CSF-1 secreted by tumor cells for TAM depletion for sufficient chemotherapy-sensitized immunotherapy., Competing Interests: Declaration of Competing Interest No conflicts of interest exist for this work., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The tumor immunosuppressive microenvironment (TIM) greatly hindered the efficacy of cancer immunotherapy. Overexpressed indoleamine 2,3-dioxygenase-1 (IDO1) in tumor tissues plays a vital role in TIM generation, and downregulation of IDO1 expression may reverse TIM. Inspired by the Watson-Crick base-pairing rule, a versatile noncationic miRNA vector (miDAC@PDA) is developed for cancer immunotherapy. Doxorubicin (DOX), adenosine triphosphate (ATP), and copper ions (Cu 2+ ) are coassembled into coordination polymer nanoparticles (DAC) and bind miRNA via the hydrogen bond interaction (miDAC) between adenine residues (ATP) and uracil residues (miRNA). Polydopamine (PDA) is deposited onto the surface of miDAC for photothermal therapy. miDAC@PDA can efficiently accumulate into tumor tissues for cellular uptake. Under laser irradiation and high intracellular GSH levels, the PDA shell of miDAC@PDA can dissociate from miDAC for miRNA release due to local hyperthermia. Cu 2+ -mediated GSH consumption and intracellular ATP release can amplify the DOX-based immunogenic cell death (ICD) cascade, together with miR-448-mediated IDO1 inhibition, and these versatile nanoplexes will not only restrain primary tumor growth but also display a remarkable abscopal effect on distant tumors. Collectively, our study provides a unique strategy for intracellular gene delivery and an inspirational approach for multimechanism cancer management.

The limited infiltration of specific T cells in an immunosuppressive microenvironment is a major challenge for cancer immunotherapy. Reversing tumor microenvironment and inducing an antitumor immune response are crucial for cancer therapy. Here, phenylboronic acid (PBA) derivative-stabilized ultrasmall platinum nanoparticles (PBA-Pt) and dextran-coated BLZ-945 nanoparticles (DNPs) were co-assembled through a pH-responsive borate ester bond to construct a versatile reversible shielding multifunctional nanoplatform (Pt@DNPs) for the first time. Pt@DNPs dissociated into two individual components, namely PBA-Pt and DNPs, in the tumor acid microenvironment. Both in vitro and in vivo studies revealed that Pt@DNPs induced immunogenic cell death (ICD) (through multimechanisms involving Pt Ⅱ release and a multienzyme catalytic process by PBA-Pt) and relieved immunosuppressive microenvironment (depletion of tumor-associated macrophages by BLZ-945), which led to tumor-associated antigen release, maturation of dendritic cells, and infiltration of cytotoxic T cells for efficient antitumor immune response against both primary tumor and pulmonary metastatic tumor nodules. Therefore, Pt@DNPs is a promising option for cancer chemo-immunotherapy. STATEMENT OF SIGNIFICANCE: A versatile reversible shielding multifunctional nanoplatform (Pt@DNPs) was engineered for the first time for combinational cancer chemo-immunotherapy. Multimechanisms involving induction of immunogenic cell death by PBA-Pt and sufficient TAM depletion by DNPs could efficiently relieve tumor immunosuppressive microenvironment and activate the antitumor immune response. The synergistic effect not only increased the infiltration of specific T cells in primary tumor, but it also induced a strong immune response against pulmonary metastatic nodules. Collectively, this nanoplatform may represent a promising strategy for combinational chemo-immunotherapy for cancers., Competing Interests: Declaration of Competing Interest No conflict of interest exists in the submission of this manuscript and this manuscript is approved by all authors for publication., (Copyright © 2021. Published by Elsevier Ltd.)

The application of combination immune-chemotherapy makes up for the limitation of monotherapy and achieves superior antitumor activity against cancer. However, combinational therapy is always restricted by poor tumor targeted drug delivery efficacy. Herein, novel T cell membrane cloaking tumor microenvironment-responsive nanoparticles (PBA modified T cell membrane cloaking hyaluronic acid (HA)-disulfide bond-vitamin E succinate/curcumin, shortened as RCM@T) were developed. T cell membrane cloaking not only serves as a protection shell for sufficient drug delivery but also acts as a programmed cell death-1(PD-1) "antibody" to selectively bind the PD-L1 of tumor cells. When RCM@T is intravenously administrated into the blood stream, it accumulates at tumor sites and responds to an acidic pH to achieve a "membrane escape effect" and expose the HA residues of RCM for tumor targeted drug delivery. RCM accumulates in the cytoplasm via CD44 receptor mediated endocytosis and intracellularly releases antitumor drug in the intracellular redox microenvironment for tumor chemotherapy. T cell membrane debris targets the PD-L1of tumor cells for tumor immunotherapy, which not only directly kills tumor cells, but also improves the CD8+ T cell level and facilitates effector cytokine release. Taken together, the as-constructed RCM@T creates a new way for the rational design of a drug delivery system via the combination of stimuli-responsive drug release, chemotherapeutical agent delivery and cell membrane based immune checkpoint blockade immunotherapy.

It is generally known that, for nanoparticles in cancer therapy, sufficient tumor penetration needs a minor particle size, while long in vivo circulation time needs a larger particle size. It is hard to balance them because they are standing on either side of a seesaw. To address these two different requirements, a dual-responsive size-shrinking nanocluster can self-adaptively respond to a complicated tumor microenvironment and transform its particulate property to overcome sequential in vivo barriers and reach a preferable antitumor activity. The nanocluster (RPSPT@SNCs) could preferentially accumulate into tumor tissue and dissociate under extracellular matrix metalloproteinase-2 (MMP-2) to release small-sized micelle formulations (RPSPTs). RPSPT possesses favorable tumor penetration and tumor targeting capability to deliver the antitumor agent paclitaxel (PTX) into deep regions of solid tumor. The intracellular redox microenvironment can also accelerate drug accumulation. The prepared RPSPT@SNCs possesses enhanced cell cytotoxicity and tumor penetration capability on MCF-7 cells and a favorable antitumor activity on the xenograft tumor mouse model.

Glioma is a fatal disease with limited treatment options and very short survival. Although chemotherapy is one of the most important strategies in glioma treatment, it remains extremely clinically challenging largely due to the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Thus, the development of nanoparticles with both BBB and BBTB penetrability, as well as glioma-targeting feature, is extremely important for the therapy of glioma. New findings in nanomedicine are promoting the development of novel biomaterials. Herein, we designed a red blood cell membrane-coated solid lipid nanoparticle (RBCSLN)-based nanocarrier dual-modified with T7 and NGR peptide (T7/NGR-RBCSLNs) to accomplish these objectives. As a new kind of biomimetic nanovessels, RBCSLNs preserve the complex biological functions of natural cell membranes while possessing physicochemical properties that are needed for efficient drug delivery. T7 is a ligand of transferrin receptors with seven peptides that is able to circumvent the BBB and target to glioma. NGR is a peptide ligand of CD13 that is overexpressed during angiogenesis, representing an excellent glioma-homing property. After encapsulating vinca alkaloid vincristine as the model drug, T7/NGR-RBCSLNs exhibited the most favorable antiglioma effects in vitro and in vivo by combining the dual-targeting delivery effect. The results demonstrate that dual-modified biomimetic nanoparticles provide a potential method to improve drug delivery to the brain, hence increasing glioma therapy efficacy.

Therapeutic outcome for the treatment of glioma was often limited due to the non-targeted nature of drugs and the physiological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). An ideal glioma-targeted delivery system must be sufficiently potent to cross the BBB and BBTB and then target glioma cells with adequate optimized physiochemical properties and biocompatibility. However, it is an enormous challenge to the researchers to engineer the above-mentioned features into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. In this study, we demonstrate a strategy for glioma targeting by encapsulating vincristine sulfate (VCR) into a naturally available apoferritin nanocage-based drug delivery system with the modification of GKRK peptide ligand (GKRK-APO). Apoferritin (APO), an endogenous nanosize spherical protein, can specifically bind to brain endothelial cells and glioma cells via interacting with the transferrin receptor 1 (TfR1). GKRK is a peptide ligand of heparan sulfate proteoglycan (HSPG) over-expressed on angiogenesis and glioma, presenting excellent glioma-homing property. By combining the dual-targeting delivery effect of GKRK peptide and parent APO, GKRK-APO displayed higher glioma localization than that of parent APO. After loading with VCR, GKRK-APO showed the most favorable antiglioma effect in vitro and in vivo. These results demonstrated that GKRK-APO is an important potential drug delivery system for glioma-targeted therapy.

Therapeutic outcome for the treatment of glioma was often limited due to the two barriers involved: the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Therefore, the development of nanocarriers that possess both BBB and BBTB permeability and glioma-targeting ability is of great importance for the chemotherapy of glioma. New frontiers in nanomedicine are advancing the research of new biomaterials. Here we constructed a natural high-density lipoprotein particle (HDL)-based drug delivery system with the dual-modification of T7 and d A7R peptide ligand (T7/ d A7R-HDL) to achieve the above goals. HDL, the smallest lipoprotein, plays a biological role and is highly suitable as a platform for delivering imaging and therapeutic agents. T7 is a seven-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma. d A7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR 2) overexpressed on angiogenesis, presenting excellent glioma-homing property. 10-Hydroxycamptothecin (HCPT), a hydrophobic anti-cancer drug, was used as the model drug in this study. By combining the dual-targeting delivery effect, the dual-modified HDL displayed higher glioma localization than that of single ligand-modified HDL or free HCPT. After loading with HCPT, T7/ d A7R-HDL showed the most favorable anti-glioma effect in vivo. These results demonstrated that the dual-targeting natural nanocarriers strategy provides a potential method for improving brain drug delivery and anti-glioma treatment efficacy.

Introduction: Specific polo-like kinase (PLK1) silencing with small interface RNA (siRNA) may be an effective approach for PLK1-overexpressed lung cancer. However, low siRNA concentration into cytoplasm of tumor tissue severely limits its application., Materials and Methods: In this study, a novel triblock copolymer methoxy poly(ethylene glycol)-poly(histidine)-poly(sulfadimethoxine) (mPEG-PHis-PSD, shorten as PHD) was synthesized and used to construct novel nonviral gene vector with cationic liposomes., Results: The resulting hybrid nanoparticles (PHD/LR) loaded with siPLK1 possessed excellent physiochemical properties. In vitro study indicated that PHD/LR could be efficiently internalized into human lung adenocarcinoma A549 cells and downregulated PLK1 protein expression to induce cell apoptosis, which was attributed to pH-induced instantaneous dissociation, efficient endo/lysosomal escape arose from PHD copolymer. Furthermore, in vivo antitumor activity demonstrated that PHD/LR could efficiently accumulated into tumor tissue and silenced PLK1 expression to possess antitumor activity., Conclusion: Taken all these together, PHD/LR was expected to be a suitable carrier for specific delivering siRNA for lung cancer therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

A multifunctional nanoparticulate system composed of methoxy poly(ethylene glycol)-poly(l-histidine)-d-α-vitamin E succinate (MPEG-PLH-VES) copolymers for encapsulation of doxorubicin (DOX) was elaborated with the aim of circumventing the multidrug resistance (MDR) in breast cancer treatment. The MPEG-PLH-VES nanoparticles (NPs) were subsequently functionalized with biotin motif for targeted drug delivery. The MPEG-PLH-VES copolymer exerts no obvious effect on the P-gp expression level of MCF-7/ADR but exhibited a significant influence on the loss of mitochondrial membrane potential, the reduction of intracellular ATP level, and the inhibition of P-gp ATPase activity of MCF-7/ADR cells. The constructed MPEG-PLH-VES NPs exhibited an acidic pH-induced increase on particle size in aqueous solution. The DOX-encapsulated MPEG-PLH-VES/biotin-PEG-VES (MPEG-PLH-VES/B) NPs were characterized to possess high drug encapsulation efficiency of approximate 90%, an average particle size of approximately 130 nm, and a pH-responsive drug release profile in acidic milieu. Confocal laser scanning microscopy (CLSM) investigations revealed that the DOX-loaded NPs resulted in an effective delivery of DOX into MCF-/ADR cells and a notable carrier-facilitated escape from endolysosomal entrapment. Pertaining to the in vitro cytotoxicity evaluation, the DOX-loaded MPEG-PLH-VES/B NPs resulted in more pronounced cytotoxicity to MCF-/ADR cells compared with DOX-loaded MPEG-PLH-VES NPs and free DOX solution. In vivo imaging study in MCF-7/ADR tumor-engrafted mice exhibited that the MPEG-PLH-VES/B NPs accumulated at the tumor site more effectively than MPEG-PLH-VES NPs due to the biotin-mediated active targeting effect. In accordance with the in vitro results, DOX-loaded MPEG-PLH-VES/B NPs showed the strongest inhibitory effect against the MCF-7/ADR xenografted tumors with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The multifunctional MPEG-PLH-VES/B nanoparticulate system has been demonstrated to provide a promising strategy for efficient delivery of DOX into MCF-7/ADR cancerous cells and reversing MDR.

Background: The objective of this work was to optimize the preparation of doxorubicin-loaded albumin nanoparticles (Dox-A-Nps) through desolvation procedures using response surface methodology (RSM). A central composite design (CCD) for four factors at five levels was used in this study., Method: Albumin nanoparticles were prepared through a desolvation method and were optimized in the aid of CCD. Albumin concentration, amount of doxorubicin, pH values, and percentage of glutaraldehyde were selected as independent variables, particle size, zeta potential, drug loading, encapsulation efficiency, and nanoparticles yield were chosen as response variables. RSM and multiple response optimizations utilizing a quadratic polynomial equation were used to obtain an optimal formulation., Results: The optimal formulation for Dox-A-Nps was composed of albumin concentration of 17 mg/ml, amount of doxorubicin of 2 mg/ml, pH value is 9 and percentage of glutaraldehyde of 125% of the theoretic amount, under which the optimized conditions gave rise to the actual average value of mean particle size (151 ± 0.43 nm), zeta potential (-18.8 ± 0.21 mV), drug loading efficiency (21.4 ± 0.70%), drug entrapment efficiency (76.9 ± 0.21%) and nanoparticles yield (82.0 ± 0.34%). The storage stability experiments proved that Dox-A-Nps stable in 4°C over the period of 4 months. The in vitro experiments showed a burst release at the initial stage and followed by a prolonged release of Dox from albumin nanoparticles up to 60 h., Conclusions: This study showed that the RSM-CCD method could efficiently be applied for the modeling of nanoparticles, which laid the foundation of the further research of immuno nanoparticles.

Tumor hypoxia is considered one of the key causes of the ineffectiveness of various strategies for cancer treatment, and the non-specific effects of chemotherapy drugs on tumor treatment often lead to systemic toxicity. Thus, we designed M1 macrophage-biomimetic-targeted nanoparticles (DOX/CAT@PLGA-M1) which contain oxygen self-supplied enzyme (catalase, CAT) and chemo-therapeutic drug (doxorubicin, DOX). The particle size of DOX/CAT@PLGA-M1 was 202.32 ± 2.27 nm (PDI < 0.3). DOX/CAT@PLGA-M1 exhibited a characteristic core-shell bilayer membrane structure. The CAT activity of DOX/CAT@PLGA-M1 was 1000 (U/mL), which indicated that the formation of NPs did not significantly affect its enzymatic activity. And in vitro drug release showed that the cumulative release rate of DOX/CAT@PLGA-M1 was enhanced from 26.93% to 50.10% in the release medium of hydrogen peroxide, which was attributed to the reaction of CAT in the NPs. DOX/CAT@PLGA-M1 displayed a significantly higher uptake in 4T1 cells, because VCAM-1 in tumor cells interacted with specific integrin (α4 and β1), and thereby achieved tumor sites. And the tumor volume of the DOX/CAT@PLGA-M1 group was significantly reduced (0.22 cm3), which further proved the active targeting effect of the M1 macrophage membrane. Above all, a novel multifunctional nano-therapy was developed which improved tumor hypoxia and obtained tumor targeting activity. [ABSTRACT FROM AUTHOR]

Therapeutic outcome for the treatment of glioma was often limited due to the non-targeted nature and low permeability of drugs across the blood-brain barrier (BBB). An ideal glioma-targeted delivery system need to traverse the BBB and then target glioma cells with adequate optimized physiochemical properties and biocompatibility. However, it is an enormous challenge to the researchers to engineer the above-mentioned features into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. In this study, we demonstrate a strategy for glioma targeting by encapsulating vincristine sulfate (VCR) into a naturally available low-density lipoprotein particles (LDL)-based drug delivery system with the modification of T7 peptide ligand (T7-LDL). LDL, endogenous lipid transporters, can specifically bind to brain endothelial cells and glioma cells via interacting with the low-density lipoprotein receptors (LDLR). T7 is a seven-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma. By combining the dual-targeting delivery effect of T7 peptide and parent LDL, T7-LDL displayed higher glioma localization than that of parent LDL. After loading with VCR, T7-LDL showed the most favorable antiglioma effect in vitro and in vivo. These results demonstrated that T7-LDL is an important potential drug delivery system for glioma-targeted therapy. [ABSTRACT FROM AUTHOR]