The emergence and dissemination of AMR have grow to be a worldwide public well being disaster and pose a profound problem to fashionable medication [1]. Since Alexander Fleming’s discovery of the antibacterial exercise of penicillin in 1928, antibiotics have been extensively employed in antimicrobial remedy. Nonetheless, the widespread and sometimes indiscriminate use of antibiotics has exerted intense selective stress on microbial populations, driving the speedy emergence and unfold of multidrug-resistant (MDR) strains [2]. Historically, antibiotics exert their results by focusing on important bacterial processes, together with protein biosynthesis, DNA replication and restore, and cell cycle development, thereby selectively inhibiting or eliminating bacterial pathogens [3]. Constructing upon this, persistent antibiotic publicity has fueled the evolution of various resistance mechanisms, together with enzymatic antibiotic degradation (e.g., β-lactamases), overexpression of efflux pumps that expel antibiotics, structural modifications of antibiotic targets (e.g., ribosomal mutations), and regulatory variations that upregulate resistance gene expression. Moreover, the formation of biofilms—advanced multicellular communities embedded inside a self-produced extracellular polymeric substance (EPS)—performs a vital function within the persistence of infections and the amplification of antibiotic resistance. The EPS matrix serves as a protecting barrier, impeding antibiotic penetration, shielding micro organism from the host immune system, and enhancing their stress tolerance [4]. Certainly, biofilm formation not solely complicates therapy methods but in addition markedly contributes to the persistence of MDR infections [5], conferring as much as a 1,000-fold improve in antibiotic tolerance [6]. Accordingly, there may be an pressing want for modern, non-antibiotic antimicrobial methods that may successfully goal each MDR micro organism and biofilms.
The escalating limitations of standard antibiotic therapies as a result of rise of AMR have catalyzed the exploration of other therapeutic modalities. Amongst these, GT has emerged as a promising non-antibiotic strategy for combating bacterial infections and biofilms. In contrast to conventional antibiotics, which generally goal particular bacterial processes vulnerable to the event of resistance, GSMs exert distinct and multifaceted antimicrobial mechanisms. These GSMs can harm bacterial membranes [7], [8], [9], inhibit bacterial respiration [10], [11], induce oxidative, nitrosative, or reactive sulfur species-mediated stress [12], [13], [14], disrupt metabolic pathways [15], intrude with DNA replication and restore [7], modulate bacterial signaling and quorum sensing (QS), and impair biofilm formation [16], [17], [18], [19]. As well as, they promote wound therapeutic by enhancing angiogenesis, modulating irritation, and stimulating tissue regeneration [20], [21], [22], thereby addressing a number of features of bacterial pathogenesis. Moreover, their small molecular dimension and excessive diffusivity allow efficient penetration of bacterial membranes and the dense EPS matrix of biofilms [23]. Importantly, these mechanisms of motion basically differ from these of antibiotics, considerably lowering the probability of resistance growth [24], [25]. Collectively, these properties spotlight GT’s potential as a next-generation antimicrobial technique.
Preclinical research have demonstrated the efficacy of GT towards MDR pathogens in numerous animal an infection fashions, underscoring its potential for scientific translation. Nonetheless, regardless of these promising outcomes, a number of crucial challenges have to be addressed earlier than GT can obtain widespread scientific software [20], [26]. GSMs’ small dimension and excessive diffusivity current substantial obstacles to reaching focused supply and enough therapeutic accumulation at an infection websites. Systemic administration typically results in non-specific biodistribution, limiting therapeutic efficacy and growing the danger of off-target results, together with potential toxicity [27]. Furthermore, monotherapy based mostly on a single GSM typically demonstrates restricted antibacterial efficacy and should carry dangers related to gasoline overdose or toxicity [8], [28]. One other main hurdle lies within the stringent dose-dependent organic results of GSMs. Their therapeutic window is commonly slim, with efficient concentrations carefully approaching poisonous thresholds. For example, NO reveals concentration-dependent biphasic results—selling vasodilation at low concentrations (<1 μM) whereas inducing cytotoxicity at greater ranges (>1 μM). This nonlinear dose-response relationship complicates exact dosing, as minor variations in GSM supply can shift outcomes from therapeutic profit to opposed results.
To deal with these limitations, appreciable analysis efforts at the moment are directed towards creating superior supply programs that allow managed, focused launch of GSMs [29]. These programs typically make the most of nanoscale vectors with tunable sizes and tailor-made physicochemical properties, which facilitate site-specific supply by way of lively or passive focusing on mechanisms [30]. Particularly, stimulus-responsive gasoline supply nanoplatforms have attracted vital consideration. These programs exploit endogenous stimuli (e.g., hydrogen peroxide (H2O2), glutathione (GSH), glucose, acidic microenvironments, or particular enzymes) or exogenous stimuli (e.g., gentle, ultrasound (US), warmth, or magnetic fields) to set off exact gasoline launch [31], [32], [33]. Leveraging the progress in stimulus-responsive supply, researchers have developed mixture methods that combine GT with different therapy modalities similar to PDT [34], PTT [35], CDT [36], and SDT [37]. These multimodal approaches develop the therapeutic panorama of GT-based interventions, providing synergistic results that improve bacterial eradication, disrupt biofilms, and modulate immune responses. Fig. 1 schematically illustrates the antibacterial mechanisms of 4 GSMs and their integration with multimodal therapies, highlighting their various roles in bacterial clearance, biofilm disruption, and immunomodulation.
This evaluate offers a complete evaluation of GT and its synergistic purposes in combating MDR micro organism and biofilms. It begins by elucidating the elemental mechanisms underlying the antimicrobial and anti-biofilm actions of every GSM, thereby establishing a mechanistic framework to contextualize their organic results. Advances in gasoline supply programs, together with cutting-edge applied sciences, are totally explored, with explicit emphasis on design ideas, practical properties, and focused supply capabilities. The therapeutic potential of GT is evaluated each as a standalone modality and together with complementary therapy methods similar to PDT, PTT, SDT, and CDT. These multimodal approaches are highlighted for his or her means to handle the restrictions of standard GT remedies, providing improved focusing on, precision, and efficacy towards bacterial infections and biofilms. As well as, the evaluate highlights key challenges that at present hinder the scientific translation of GT, together with points associated to supply effectivity, security, and regulatory approval. By offering a complete synthesis of latest progress and outlining future analysis instructions, this evaluate bridges the fields of microbiology, nanomedicine, and supplies science, providing priceless insights to information the event of safer, more practical nano-antibacterial platforms for overcoming AMR.
