As a result of excessive efficacy and organic security, fuel remedy has been acknowledged as “inexperienced” remedy technique[1], [2]. In gasotransmitter household, the prominently involved nitric oxide (NO) performs a necessary function in physiological actions, together with neurotransmission, immune response, and angiogenesis[3], [4]. In the meantime, NO displays two-sided pharmacological capabilities in regulating tumor development[5], [6]. At low concentrations, NO can promote the survival and proliferation of tumor cells by regulating the antioxidant impact[7], [8]. At excessive concentrations, NO can inhibit tumor cell development by means of the pathways of mitochondria harm, apoptotic enhancement, and hypoxic remittance[9], [10]. Because of this, tumor suppression requires additional exogenous NO supplementation by means of supply of NO donor, specifically, pure L-arginine (L-Arg)[11], [12]. Within the H2O2-rich tumor microenvironment, L-Arg might be oxidized into NO, which omits the unspecific launch of NO in regular tissues[13], [14]. Nevertheless, the restricted focus of endogenous H2O2 in tumor cells (50 × 10-6 to 100 × 10-6 M)[15] restricts the oxidization of L-Arg into NO. To advertise NO technology, co-delivery of glucose oxidase (GOx) and L-Arg was most popular by advantage of two-step catalytic response in tumor microenvironment[16], [17]. For the primary catalytic stage, GOx consumed the vitality supply of glucose to starve tumor cells and generate H2O2. Subsequently, H2O2 additional triggers the second stage of catalytic response by oxidization of L-Arg into NO.
Certainly, the co-loading of GOx and L-Arg within the nanoplatform can generate a cascade nanobioreactor, enabling synergistic hunger/fuel remedy. For instance, Fan and colleagues[18] adopted hole mesoporous silica nanoparticles to immobilize GOx and L-Arg. This nanobioreactor clearly intervened tumor development by cooperative anticancer results of glucose consumption and NO technology. As GOx catalyzes glucose in each regular and most cancers cells, the modification of concentrating on ligand on nanobioreactor is of nice significance to advertise anticancer effectivity and decrease potential systemic poisonous results. On this regard, Fu and colleagues[14] employed hyaluronic acid (HA)-coated calcium phosphate nanoparticles as carriers of GOx and L-Arg. With the concentrating on skill of HA, this nanobioreactor can preferentially focus in tumor tissue overexpressing glycoprotein CD44 to curtail the tumor quantity. Equally, Zhai and Peng constructed folic acid-targeted L-Arg/GOx@manganese oxide nanoparticles to ensure good selectivity towards folic acid receptor-overexpressed most cancers cells[19], [20]. Nevertheless, along with the a number of difficult preparation routes and potential unwanted effects of nanocarriers, the effectivity of most out there nanobioreactors to transform L-Arg into NO in tumor microenvironment is unsatisfactory because of the extreme ingredient leakage from nanobioreactors, impaired enzyme exercise throughout chemical preparation, and comparatively low oxidation potential (?+1.8 V) of H2O2.
DNA nanoflowers (DNF) synthesized by rolling circle replication (RCA) are a quickly rising class of DNA nanostructures[21], [22], [23], providing potential options to handle these challenges. RCA is an isothermal enzymatic amplification methodology, through which DNA polymerase produces ultralong DNA strands by repeating enhances of a custom-made template[24], [25], [26]. Throughout RCA course of, the generated DNA strands are prone to mediate the crystallization of response byproduct magnesium pyrophosphate, resulting in the formation of flower-shaped DNA-inorganic composites, termed DNF. Given the distinctive options, together with glorious biocompability, template programmability, hierarchical construction, and nuclease tolerance, DNF have proven a variety of biomedical functions, particularly in concentrating on bioimaging[27], [28], protein immobilization[29], [30], and drug supply[31], [32]. Regardless of their promise for nanobioreactor design, to one of the best of our information, DNF haven’t but been explored within the area of cascade catalysis that’s able to selling fuel technology for high-performance synergistic remedy of tumors.
On this examine, a storage-stable cascade DNA nanobioreactor is synthesized by way of one-pot RCA, throughout which the polymerized DNA molecules and abundance of magnesium ions present many electrostatic and coordinative interplay websites for each L-Arg and GOx, enabling excessive loading effectivity, superior storage stability, and enhanced protein stability. After encoding with repetitive human epidermal development issue receptor 2 (HER2)-targeting aptamer, this nanobioreactor particularly accumulates into HER2-overexpressing tumor website to set off the cascade catalysis from conversion of glucose into H2O2 utilizing GOx to oxidization of L-Arg into NO by H2O2. Through the cascade catalytic course of, ultrasound (US) irradiation decomposes H2O2 into extremely reactive oxygenated species for promoted NO manufacturing, finally attaining augmented outcomes of synergistic hunger/chemodynamic/fuel remedy.