Heart-targeted amelioration of sepsis-induced myocardial dysfunction by microenvironment responsive nitric oxide nanogenerators in situ

Abstract

Background A balanced endogenous level of bioavailable nitric oxide (NO) plays a key role in maintaining cardiovascular homeostasis. The bioactive NO level in the cardiomyocytes was much reduced during sepsis. However, it is clinically challenging for the NO gas therapy due to the lack of spatial and temporal release system with precise control. The purpose of this study is to design a NO-releasing biomaterial with heart-targeted capability responsive to the infectious microenvironment, thus ameliorating lipopolysaccharide (LPS)-induced cardiac dysfunction. Results The heart-targeted NO delivery and in situ releasing system, PCM-MSN@LA, was synthesized using hollow mesoporous silica nanoparticles (MSN) as the carrier, and L-arginine (LA) as the NO donor. The myocardial delivery was successfully directed to heart by specific peptide (PCM) combined with low-intensity focused ultrasound (LIFU) guidance. The myocardial system synthesized NO from the LA released from PCM-MSN@LA in the presence of increased endogenous nitric oxide synthase (NOS) activity induced by LPS. This targeted NO release in situ achieved extraordinary protective effects against LPS-challenged myocardial injury by reducing the recruitment of inflammatory cells, inhibiting oxidative stress and maintaining the mitochondria integrity. In particular, this protection was not compromised by simultaneous circulation collapse as an adverse event in the context. Conclusions PCM-MSN@LA + LIFU exhibited extraordinary cardioprotective effects against severe sepsis in the hearts of LPS-treated animals without the side effect of NO diffusion. This technology has great potential to be served as a novel therapeutic strategy for sepsis-induced myocardial injury.

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

“…Heart repair and regeneration NA@MEV [ 172] L-arginine -98.06 -3.8 MitoN Myocardial dysfunction PCM-MSN@LA [ 246] Specific peptide -186.67 -6.23 L-arginine MI Mito-Fenozyme [ 242] EPR effect TPP 6.5 21.8 MnO 2 nanozyme MI SSSe NPs [ 173] --20-40 -7.79 Se NPs MI CsA@PLGE-PEG-SS31 [225] -SS31 54 14.5 CsA Myocardial I/R injury PEP-TPP-mitochondrial compound [ 192] PEP TPP --Mitochondria…”

Applications of peptides in nanosystems for diagnosing and managing bacterial sepsis

“…Organ targeting peptides Among the strategies for incorporating peptides as targeting moieties on nanosystems surface, a notable approach is targeting specific organs' tissues and cells. Organ-specific peptides allow for accurate drug delivery to particular organs during sepsis, offering a mechanism to rescue key organs at high risk of damage and failure [192,200]. In this regard, Huang et al engineered zeolite imidazolate framework-8 nanoparticles coated with renal tubular epithelial cell membrane and modified with a kidney targeting peptide (KCSAV-PLC) to promote specific drug uptake by renal tubular cells.…”

“…Utilizing a similar approach, Ouyang and coworkers designed hollow mesoporous silica nanoparticles (PCM-MSN@LA) loaded with L-arginine (LA) as nitric oxide (NO)-releasing agent and modified with primary cardiomyocytes specific peptide (PCM) for heart tissues-targeted delivery to combat LPS-induced cardiac injury [192]. As illustrated in Fig.…”

“…Furthermore, PCM-MSN@LA combined with LIFU significantly reduced inflammatory cells recruitment, mitochondrial dysfunction, and oxidative Fig. 12 Design of heart-targeting L-arginine loaded mesoporous silica nanoparticles (PCM-MSN@LA) and its combined application with low-intensity focused ultrasound (LIFU) to prevent cardiac damage in mice [192] Page 30 of 37 stress in LPS-induced septic mice's cardiac tissues, thus prevented myocardial injury and cardiac dysfunction. We believe their strategy is promising and holds great potential for preventing sepsis-induced cardiac dysfunction in clinical settings.…”

VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis

“…Mainly, SIMD leads to a decline in myocardial contractility, inadequate organ perfusion, and multiple organ failure. Inflammatory responses, Ca 2+ dysregulation, mitochondrial dysfunction, autonomic dysfunction, excessive production of nitric oxide (NO), and apoptosis are recognized mechanisms of SIMD 7 - 11 . While conventional therapies like norepinephrine, calcium sensitizer, and beta-blockers have achieved some progress in treating SIMD, their therapeutic effects remain less than ideal 12 - 14 .…”