bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2023‒01‒15
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Sci Transl Med. 2023 Jan 11. 15(678): eabl7895
      Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src-signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.
  2. ACS Nano. 2023 Jan 10.
      Effective drug delivery and prevention of postoperative recurrence are significant challenges for current glioblastoma (GBM) treatment. Poor drug delivery is mainly due to the presence of the blood-brain barrier (BBB), and postoperative recurrence is primarily due to the resistance of GBM cells to chemotherapeutic drugs and the presence of an immunosuppressive microenvironment. Herein, a biomimetic nanodrug delivery platform based on endogenous exosomes that could efficiently target the brain without targeting modifications and co-deliver pure drug nanomicelles and immune adjuvants for safe and efficient chemo-immunotherapy against GBM is prepared. Inspired by the self-assembly technology of small molecules, tanshinone IIA (TanIIA) and glycyrrhizic acid (GL), which are the inhibitors of signal transducers and activators of transcription 3 from traditional Chinese medicine (TCM), self-assembled to form TanIIA-GL nanomicelles (TGM). Endogenous serum exosomes are selected to coat the pure drug nanomicelles, and the CpG oligonucleotides, agonists of Toll-like receptor 9, are anchored on the exosome membrane to obtain immune exosomes loaded with TCM self-assembled nanomicelles (CpG-EXO/TGM). Our results demonstrate that CpG-EXO/TGM can bind free transferrin in blood, prolong blood circulation, and maintain intact structures when traversing the BBB and targeting GBM cells. In the GBM microenvironment, the strong anti-GBM effect of CpG-EXO/TGM is mainly attributed to two factors: (i) highly efficient uptake by GBM cells and sufficient intracellular release of drugs to induce apoptosis and (ii) stimulation of dendritic cell maturation and induction of tumor-associated macrophages polarization by CpG oligonucleotides to generate anti-GBM immune responses. Further research found that CpG-EXO/TGM can not only produce better efficacy in combination with temozolomide but also prevent a postoperative recurrence.
    Keywords:  Glioblastoma; blood−brain barrier; chemo-immunotherapy; self-assembled nanomicelles; serum exosomes
  3. J Control Release. 2023 Jan 10. pii: S0168-3659(23)00021-4. [Epub ahead of print]
      Atherosclerosis is a chronic disease initiated by lipid-mediated vascular inflammation. From the perspective of conventional treatment, it is difficult to achieve good therapeutic effects via regulation of a single lipid or anti-inflammatory effects. Herein, we designed an amphiphilic low molecular weight heparin-unsaturated fatty acid conjugate (LMWH-uFA) that acted as both an antiatherosclerotic agent and a nanocarrier with self-delivery properties. Structurally, LMWH-uFA self-assembled to form micelles with LMWH as the shell and uFA as the core, without any additives, which guaranteed their biosafety. Functionally, the hydrophilic segment, LMWH, prevented monocyte adhesion to inhibit early vascular inflammation, and the hydrophobic segment, uFA, could participate in the regulation of blood lipids. The anti-inflammatory drug rapamycin (RAP) was encapsulated in the micellar core, which improved its water solubility, and cooperated with LMWH to achieve targeted blockade of the vascular inflammation cascade at P-selectin. The three treatment modules, LMWH, uFA and RAP, were integrated into one system for different therapeutic targets in anticipation of better efficacy. In an atherosclerosis mouse model, RAP-loaded NPs significantly reduced the plaque area and showed satisfactory curative effects, which were related to the targeting of lipid regulation and inflammation. Thus, these modular micellar nanoparticles offer a promising approach for the clinical treatment of atherosclerosis.
    Keywords:  Atherosclerosis; Low-molecular-weight heparin; Micelles; P-selectin; Unsaturated fatty acid
  4. Adv Mater. 2023 Jan 13. e2211579
      Induction of immunogenic cell death (ICD) plays crucial roles in cancer immunotherapy, whereas its efficacy is severely compromised by redundant antioxidant defenses in cancer cells and aberrant lipid metabolism in immunosuppressive cell populations. Herein, we find that hollow mesoporous CuS nanoparticles (NPs) possess an intrinsic capacity of inhibiting the glutathione peroxidase 4 (GPX4). When loaded with an inhibitor of the ferroptosis suppressor protein 1 (FSP1), these NPs block two parallel redox systems and cooperate with near-infrared irradiation to reinforce ICD. We further fabricate a hydrogel co-delivering cancer cell-targeting CuS NPs and immunosuppressive cell-targeting sulfo-N-succinimidyl oleate (SSO) for spatiotemporal lipid intervention. While the CuS NPs augment ICD via synergistic lipid peroxidation, SSO reinstates immune perception via lipid metabolic reprogramming, thereby coordinately triggering robust innate and adaptive immunity to restrain tumor growth, relapse and metastasis. Our study provides an immunometabolic therapy via orchestrated lipid modulation in the tumor milieu. This article is protected by copyright. All rights reserved.
    Keywords:  CuS nanoparticles; composite hydrogel; immunogenic cell death; lipid metabolism reprogramming; lipid peroxidation
  5. Adv Healthc Mater. 2023 Jan 09. e2202695
      Methionine metabolism has a significant impact on T cells' survival and activation even in comparison to arginine, a well-documented amino acid in metabolic therapy. However, hydrophilic methionine is hardly delivered into TME due to difficult loading and rapid diffusion. Herein, the labeling assembly of methionine into nanoparticle is developed to overcome high hydrophilicity for mild-heat mediated immunometabolic therapy. The strategy is to firstly label methionine with protocatechualdehyde (as the tag) via reversible Schiff-base bond, and then drive nano-assembly of methionine (MPC@Fe) mediated by iron ions. In this fashion, a loading efficiency of 40% and assembly induced photo-thermal characteristics could be achieved. MPC@Fe can accumulate persistently in tumor up to 36 h due to tumor-selective aggregation in acidic TME. A mild heat of 43°C on tumor by light irradiation stimulated the immunogenic cell death and effectively generated CD8+ T cells. Notably, MPC@Fe assisted by mild heat promoted 4.2-fold of tumor-infiltrating INF-γ+ CD8+ T cells, leading to an inhibition ratio of 27.3-fold versus the free methionine. Such labeling assembly provides a promising methionine delivery platform to realize mild heat mediated immunometabolic therapy, and is potentially extensible to other amino acids. This article is protected by copyright. All rights reserved.
    Keywords:  T cells survival and activation; immunometabolic therapy; labeling assembly; methionine delivery
  6. J Control Release. 2023 Jan 07. pii: S0168-3659(23)00010-X. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.
    Keywords:  Gas therapy; Gemcitabine chemotherapy; Gold nanocages; Pancreatic cancer; Photoacoustic tomography
  7. Adv Mater. 2023 Jan 10. e2207744
      Nebulization is the most widely used respiratory delivery technique with non-invasive properties. However, nebulized drugs often fail to function due to the excretion and immune clearance of the respiratory system. Here, inspired by pollen in nature, novel shell-core aerosol particles (APs) capable of Brownian Motion were constructed for respiratory delivery. Drugs-loaded poly(lactic-co-glycolic acid) nanoparticles were prepared by emulsification to form the inner core, and the membranes of macrophages were extracted to form the outer shell. The optimized size and the shell-core structure endowed APs with Brownian Motion and atomization stability, thus enabling the APs to reach the bronchi and alveoli deeply for effective deposition. The camouflage of macrophage membranes equipped the APs with immune evasion. In vitro experiments proved that deferoxamine (DFO) loaded APs (DFO@APs) could promote the angiogenesis of human umbilical vein endothelial cells. A hyperoxia-induced bronchopulmonary dysplasia (BPD) model was constructed to validate the efficiency of DFO@APs. In BPD mice, DFO@APs could release DFO in the alveolar interstitium, thus promoting the reconstruction of microvasculature, ultimately inducing lung development for treating BPD. In conclusion, this study developed "pollen"-inspired shell-core aerosol particles capable of Brownian Motion, which provides a novel idea and theoretical basis for respiratory administration. This article is protected by copyright. All rights reserved.
    Keywords:  Atomization; Bronchopulmonary dysplasia; Hif-1; Respiratory diseases; Vascularization
  8. Nat Genet. 2023 Jan;55(1): 19-25
      Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution1-11. However, broad clinical application of these methods remains challenging, due to several practical and preanalytical challenges that are incompatible with typical clinical care workflows, namely the need for relatively large, fresh tissue inputs. In the present study, we show that multimodal, single-nucleus (sn)RNA/T cell receptor (TCR) sequencing, spatial transcriptomics and whole-genome sequencing (WGS) are feasible from small, frozen tissues that approximate routinely collected clinical specimens (for example, core needle biopsies). Compared with data from sample-matched fresh tissue, we find a similar quality in the biological outputs of snRNA/TCR-seq data, while reducing artifactual signals and compositional biases introduced by fresh tissue processing. Profiling sequentially collected melanoma samples from a patient treated in the KEYNOTE-001 trial12, we resolved cellular, genomic, spatial and clonotype dynamics that represent molecular patterns of heterogeneous intralesional evolution during anti-programmed cell death protein 1 therapy. To demonstrate applicability to banked biospecimens of rare diseases13, we generated a single-cell atlas of uveal melanoma liver metastasis with matched WGS data. These results show that single-cell genomics from archival, clinical specimens is feasible and provides a framework for translating these methods more broadly to the clinical arena.
  9. Nat Commun. 2023 Jan 06. 14(1): 108
      Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.
  10. Adv Mater. 2023 Jan 10. e2211363
      Fast and accurate detection of microbial cells in clinical samples is highly valuable but remains a challenge. Here, a simple, culture-free diagnostic system is developed for direct detection of pathogenic bacteria in water, urine and serum samples using an optical colorimetric biosensor. It consists of printed nanoarrays chemically conjugated with specific antibodies that exhibits distinct color changes after capturing target pathogens. By utilizing the internal capillarity inside an evaporating droplet, target preconcentration is achieved within a few minutes to enable rapid identification and more efficient detection of bacterial pathogens. More importantly, the scattering signals of bacteria can be significantly amplified by the nanoarrays due to strong near-field localization, which supports a visualizable analysis of the growth, reproduction and cell activity of bacteria at the single-cell level. Finally, in addition to high selectivity, this nanoarray-based biosensor is also capable of accurate quantification and continuous monitoring of bacterial load on food over a broad linear range, with a detection limit of 10 CFU mL-1 . This work provides an accessible and user-friendly tool for point-of-care testing of pathogens in many clinical and environmental applications, and possibly enables a breakthrough in early prevention and treatment. This article is protected by copyright. All rights reserved.
    Keywords:  bacterial diagnostics; biosensor; light scattering; nanoarray; printing
  11. ACS Nano. 2023 Jan 09.
      Responsive nanosystems for tumor treatment with high specificity and sensitivity have aroused great attention. Herein, we develop a tumor microenvironment responsive and near-infrared (NIR)-activatable theranostic nanoreactor for imaging-guided anticancer therapy. The nanoreactor (SnO2-x@AGP) is comprised of poly(vinylpyrrolidine) encapsulated hollow mesoporous black SnO2-x nanoparticles coloaded with glucose oxidase (GOx) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). The constructed nanoreactor can be specifically activated through endogenous H2O2 by an NIR-mediated "bursting-like" process to enhance its imaging and therapeutic functions. Black SnO2-x with abundant oxygen vacancies expedites effective separation of electron-hole pairs from energy-band structure and endows them with strong hyperthermia effect upon NIR laser irradiation. The generating toxic H2O2 with the assistance of GOx provides SnO2-x@AGP with the capacity of oxidative stress therapy. Ascended H2O2 can activate ABTS into ABTS•+. ABTS•+ not only possesses significant NIR absorption properties, but also disrupts intracellular glutathione to generate excessive reactive oxygen species for improved phototherapy, leading to more effective treatment together with oxidative stress therapy. Thus, SnO2-x@AGP with NIR-mediated and H2O2-activated performance presents tumor inhibition efficacy with minimized damage to normal tissues. These outstanding characteristics of SnO2-x@AGP bring an insight into the development of activatable nanoreactors for smart, precise, and non-invasive cancer theranostics.
    Keywords:  cancer phototherapy; multimodal imaging; nanoreactor; near-infrared light; responsive nanosystems
  12. ACS Nano. 2023 Jan 09.
      Serum proteins bind and form a dynamic protein corona around nanoparticles (NPs) that have been injected into the mammalian vasculature. Several fundamental studies have shown that apolipoproteins are prominent components of the NP corona. Since apolipoproteins control the distribution of lipoproteins, they may also control the distribution of NPs. Indeed, apolipoprotein affinity for NPs has been recently taken advantage of to deliver CRISPR reagents encapsulated in NPs to cells that express particular lipoprotein receptors. In this scenario, an apolipoprotein binds an NP and the resulting apolipoprotein-NP complex binds a cell that expresses the (apo)lipoprotein receptor. But the NP will be diverted from the target cell if it does not express the (apo)lipoprotein receptor. This may hamper NP treatment of diseases. Therefore, we must understand the kinetics of apolipoprotein-NP affinity and how apolipoprotein-NP interactions affect NP biodistribution. In this Perspective, we discuss the evolving topic of apolipoprotein-NP interactions, which is of great interest for all NP-based disease treatments. Many properties of apolipoprotein-NP complexes are yet to be determined and will have a significant impact on NP efficacy for many NP-based treatments in animal models and in the clinic.
    Keywords:  ApoE; LDLR; apolipoprotein; lipid nanoparticle; lipoprotein; liver; nanoparticle
  13. Proc Natl Acad Sci U S A. 2023 Jan 17. 120(3): e2208377120
      Nanoparticles or drug carriers which can selectively bind to cells expressing receptors above a certain threshold surface density are very promising for targeting cells overexpressing specific receptors under pathological conditions. Simulations and theoretical studies have suggested that such selectivity can be enhanced by functionalizing nanoparticles with a bimodal polymer monolayer (BM) containing shorter ligated chains and longer inert protective chains. However, a systematic study of the effect of these parameters under tightly controlled conditions is still missing. Here, we develop well-defined and highly specific platforms mimicking particle-cell interface using surface chemistry to provide a experimental proof of such selectivity. Using surface plasmon resonance and atomic force microscopy, we report the selective adsorption of BM-functionalized nanoparticles, and especially, a significant enhanced selective behavior by using a BM with longer protective chains. Furthermore, a model is also developed to describe the repulsive contribution of the protective brush to nanoparticle adsorption. This model is combined with super-selectivity theory to support experimental findings and shows that the observed selectivity is due to the steric energy barrier which requires a high number of ligand-receptor bonds to allow nanoparticle adsorption. Finally, the results show how the relative length and molar ratio of two chains can be tuned to target a threshold surface density of receptors and thus lay the foundation for the rational design of BM-functionalized nanoparticles for selective targeting.
    Keywords:  bimodal brush; functionalization; nanoparticle; receptor surface density; selectivity