RESUMO
Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, the practical application is still suffering from the decreased function, inadequate infiltration, and immunosuppressive microenvironment in solid tumor. Herein, we construct the light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on NK cell surface, it forms a catalytic array with light-harvesting capabilities. This functionality transforms NK cells into cellular factories, capable of catalyzing the production of active agents in a light-controlled manner. The NK@p-Fe can generate active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, the NK@p-Fe can also bioorthogonally catalyze to produce FDA approved immune agonist, imiquimod (IMQ). The activated immune agonist plays a dual role by inducing DC maturation for NK cells activation and reshaping tumor immunosuppressive microenvironment for NK cells infiltration. This work represents a paradigm for modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis.
RESUMO
Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn2+ ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen (1O2) and oxidize ß-amyloid (Aß) to inhibit aggregation, consequently attenuating Aß neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aß selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aß plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD.
RESUMO
Despite the demonstrated importance of DNA G-quadruplexes (G4s) in health and disease, technologies to readily manipulate specific G4 folding for functional analysis and therapeutic purposes are lacking. Here we employ G4-stabilizing protein/ligand in conjunction with CRISPR to selectively facilitate single or multiple targeted G4 folding within specific genomic loci. We demonstrate that fusion of nucleolin with a catalytically inactive Cas9 can specifically stabilize G4s in the promoter of oncogene MYC and muscle-associated gene Itga7 as well as telomere G4s, leading to cell proliferation arrest, inhibition of myoblast differentiation and cell senescence, respectively. Furthermore, CRISPR can confer intra-G4 selectivity to G4-binding compounds pyridodicarboxamide and pyridostatin. Compared with traditional G4 ligands, CRISPR-guided biotin-conjugated pyridodicarboxamide enables a more precise investigation into the biological functionality of de novo G4s. Our study provides insights that will enhance understanding of G4 functions and therapeutic interventions.
Assuntos
Sistemas CRISPR-Cas , Quadruplex G , Nucleolina , Proteínas de Ligação a RNA , Humanos , Ligantes , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ácidos Picolínicos/farmacologia , Ácidos Picolínicos/química , Proliferação de Células/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Animais , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Proteína 9 Associada à CRISPR/metabolismo , Proteína 9 Associada à CRISPR/genética , Regiões Promotoras Genéticas , Telômero/metabolismo , Telômero/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piridinas/farmacologia , Piridinas/química , DNA/metabolismo , DNA/genética , Camundongos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Células HEK293 , Mioblastos/metabolismo , Mioblastos/citologia , AminoquinolinasRESUMO
Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic modulation model of mitochondrial DNA (mtDNA) is selected because mtDNA establishes a relative hypermethylation stage under oxidative stress, which impairs the mitochondrion-based therapeutic effect during cancer therapy. Herein, we design a new biocompatible hydrogen-bonded organic framework (HOF) for a HOF-based mitochondrion-targeting bioorthogonal platform TPP@P@PHOF-2. PHOF-2 can activate a prodrug (pro-procainamide) in situ, which can specifically inhibit DNA methyltransferase 1 (DNMT1) activity and remodel the epigenetic modification of mtDNA, making it more susceptible to ROS damage. In addition, PHOF-2 can also catalyze artemisinin to produce large amounts of ROS, effectively damaging mtDNA and achieving better chemodynamic therapy demonstrated by both in vitro and in vivo studies. This work provides new insights into developing advanced bioorthogonal therapy and expands the applications of HOF and bioorthogonal catalysis.
Assuntos
DNA Mitocondrial , Epigênese Genética , Mitocôndrias , Espécies Reativas de Oxigênio , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , DNA Mitocondrial/genética , Epigênese Genética/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ligação de Hidrogênio , Animais , Camundongos , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologiaRESUMO
6-Nitrobenzo[cd]indole-2(1H)-ketone (compound C2) exhibits an excellent germicidal effect against methicillin-resistant Staphylococcus aureus (MRSA). Mechanism studies show that C2 induces ROS over-production, cell membrane damage, and ATP and virulence factor down-regulation in bacteria. More importantly, C2 can inhibit biofilm formation and accelerate wound healing in a mouse infection model induced by MRSA.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Camundongos , Staphylococcus aureus , Antibacterianos/farmacologia , Cetonas/farmacologia , Biofilmes , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Modelos Animais de Doenças , Indóis/farmacologiaRESUMO
The disposal of iron-rich sludge by landfill or incineration poses environmental risks and wastes resources. The utilization of iron-rich sludge for magnetic material preparation offers a sustainable and resource-efficient solution for its disposal. Herein, self-endowed magnetic photocatalysts were initially prepared by pyrolysis using iron-rich sludge without any additives. The photocatalysts performance were evaluated for tetracycline degradation, with the highest degradation rate of 95.3 % at a concentration of 10 mg·L-1 (pH = 7) within 5 h being achieved for the photocatalyst prepared at 800 °C. The reactive radical species in the photocatalysis process were confirmed to be â¢OH and O2â¢- activated by ferrous oxygen species under light irradiation. Furthermore, quinone-like structures induced bound persistent free radicals, which emerged as the predominant factors influencing 1O2 formation. The employed photocatalyst can be efficiently separated and recovered owing to its magnetism. This work presents an economic solution for antibiotic removal using waste iron-rich sludge.