The tumor microenvironment (TME) is a extremely advanced and dynamic ecosystem that performs a important function in most cancers development[1], [2]. It consists not solely of malignant tumor cells but in addition stromal cells, immune cells, blood vessels, and extracellular matrix (ECM) elements, which work together in intricate methods to advertise tumor development, metastasis, and therapeutic resistance[3]. One of the outstanding options of the TME is its altered metabolic state, which is characterised by hypoxia, acidosis, and a shift towards elevated lactate manufacturing on account of enhanced glycolysis—a phenomenon generally known as the Warburg impact[4]. This metabolic reprogramming is important for tumor cell proliferation, immune evasion, and therapy resistance, all of which complicate the effectiveness of conventional most cancers therapies[5], [6].
In mild of those distinctive traits, enzyme dynamic remedy (EDT) has emerged as a promising therapeutic technique[7], [8]. EDT makes use of the catalytic exercise of particular enzymes to generate reactive oxygen species (ROS) or different bioactive molecules, disrupting the redox stability in tumor cells, inducing DNA injury, and selling apoptosis[9], [10], [11], [12], [13]. The coordinated actions of oxidases and peroxidases play important roles in sustaining mobile homeostasis and stopping oxidative stress, notably in mitochondria[14] and peroxisomes[15]. A lot of the analysis on catalytic therapies focuses on utilizing cascade catalytic techniques to generate ROS, which in flip disrupts the redox stability within the TME and induces DNA injury in tumor cells[16], [17]. On this context, our analysis group has spent over a decade investigating cascade enzymatic gelation methods and their organic results[18], [19], [20], [21], [22]. Impressed by the catalytic mechanisms of neutrophils and organelles like peroxisomes, we now have proposed a novel EDT method that leverages an enzymatic cascade response involving superoxide dismutase (SOD) and chloroperoxidase (CPO) for efficient tumor remedy[20]. Moreover, peroxisome-mimetic lactate oxidase (LOx) and catalase (CAT)-co-loaded nanogels have been developed for synergistic EDT and photodynamic remedy (PDT)[18].
Along with these metabolic alterations, most cancers cells exhibit genomic instability, which serves as a trademark of tumor development[23], [24]. These cells show uncontrolled development on account of elements corresponding to self-sufficient development indicators, insensitivity to anti-growth indicators, resistance to cell dying, and genomic instability[25], [26]. The TME additional contributes to this course of, as tumor cells work together with regular cells, corresponding to fibroblasts and endothelial cells, to advertise development and division. Whereas conventional most cancers therapies like chemotherapy, radiation, and PDT goal the cell cycle and induce DNA injury, this injury typically prompts DNA restore mechanisms, permitting most cancers cells to restore themselves and proceed proliferating[11], [12], [27], [28], [29]. The activation of DNA restore pathways in response to remedy results in drug resistance, which has been a significant problem in most cancers therapy. Some therapeutic methods purpose to inhibit DNA restore and induce cell cycle arrest to beat this challenge[30], [31], [32], [33]. For instance, the usage of antisense oligonucleotides (ASO-miR21) to focus on microRNA-21 (miR21), which is overexpressed in lots of tumors and inhibits apoptosis, has proven promise in enhancing apoptosis and interfering with DNA replication[34], [35], [36]. These findings underscore the significance of concurrently inhibiting tumor cell proliferation and disrupting their DNA restore pathways to realize more practical therapy outcomes.
Constructing on the TME’s distinctive metabolic options and the dynamics of apoptosis and proliferation, we suggest a novel therapeutic technique that mixes EDT with gene remedy. This method leverages a cascade oxidase-peroxidase system to concurrently induce tumor cell dying and inhibit DNA restore mechanisms, guided by the ideas of apoptosis and proliferation within the TME. Particularly, lactate oxidase (LOx) and CPO are employed to advertise tumor cell apoptosis by way of lactate metabolism, whereas ASO-miR21 inhibits tumor cell proliferation. Mimicking pure multienzyme advanced meeting, we engineered a steady, hyperactive, and spatially ordered enzyme-gene platform (ASO-miR21/DLC-NGs) through a polysaccharide-confined multi-enzyme co-assembly technique coupled with polymerization reinforcement (Scheme 1). Exact management over service dimensions (nanoscale to microscale) and crosslinking density addresses the constraints of standard multienzyme techniques, together with instability and inefficient substrate diffusion. Environment friendly ASO-miR21 loading and transfection had been achieved by way of floor cost modulation. This platform permits coordinated enzyme positioning, optimized transport channels, and managed gene supply, collectively facilitating reactive oxygen species (ROS)-mediated redox stability reversal. Moreover, miR21 downregulation synergistically inhibits tumor proliferation. In the end, this synergistic coupling of gene and metabolic pathways by way of cascade enzyme biocatalytic remedy supplies a promising method for enhanced most cancers therapy.
