Applications of peptides in nanosystems for diagnosing and managing bacterial sepsis

Abstract

Sepsis represents a critical medical condition stemming from an imbalanced host immune response to infections, which is linked to a significant burden of disease. Despite substantial efforts in laboratory and clinical research, sepsis remains a prominent contributor to mortality worldwide. Nanotechnology presents innovative opportunities for the advancement of sepsis diagnosis and treatment. Due to their unique properties, including diversity, ease of synthesis, biocompatibility, high specificity, and excellent pharmacological efficacy, peptides hold great potential as part of nanotechnology approaches against sepsis. Herein, we present a comprehensive and up-to-date review of the applications of peptides in nanosystems for combating sepsis, with the potential to expedite diagnosis and enhance management outcomes. Firstly, sepsis pathophysiology, antisepsis drug targets, current modalities in management and diagnosis with their limitations, and the potential of peptides to advance the diagnosis and management of sepsis have been adequately addressed. The applications have been organized into diagnostic or managing applications, with the last one being further sub-organized into nano-delivered bioactive peptides with antimicrobial or anti-inflammatory activity, peptides as targeting moieties on the surface of nanosystems against sepsis, and peptides as nanocarriers for antisepsis agents. The studies have been grouped thematically and discussed, emphasizing the constructed nanosystem, physicochemical properties, and peptide-imparted enhancement in diagnostic and therapeutic efficacy. The strengths, limitations, and research gaps in each section have been elaborated. Finally, current challenges and potential future paths to enhance the use of peptides in nanosystems for combating sepsis have been deliberately spotlighted. This review reaffirms peptides' potential as promising biomaterials within nanotechnology strategies aimed at improving sepsis diagnosis and management.

Keywords: Drug delivery; Nanosystem; Peptide; Sepsis; Sepsis diagnosis; Sepsis management.

Fig. 1

Immune responses in sepsis owing to infection. Illustration of converting to sepsis from infection. Immune cells activation results in the overproduction of inflammatory mediators that induce detrimental changes in cells and tissues, leading to multiorgan dysfunction and failure (SOFA: sequential organ failure assessment; EWS: early warning score; iNOS: inducible nitric oxide synthase; ARDS: acute respiratory distress syndrome) (Adopted with permission from [55]

Fig. 2

A schematic illustration of various applications of peptides in nanotools for sepsis diagnosis and management (NPs: Nanoparticles; AIPs: Anti-inflammatory Peptides; AMPs: Antimicrobial Peptides) (Created with BioRender.com)

Fig. 3

Detection of S. aureus and L. monocytogenes using a two-step approach paired with m-qPCR, utilizing the MBs-S~Bio-den-Van~bacteria complex [123]

Fig. 4

Experimental setup of separation of bacteria from blood using SPION-APTES-Pep (Adopted from [118])

Fig. 5

Representation of the process from phage display to manufacturing of the SERS substrate. A Insertion of the cysteine-rich peptide into the major PV111 protein domain of the M13KE phage using two restriction enzymes (BtgZI and HinP1I). B The colony PCR analysis on a 1% agarose gel confirms the effective integration of the cysteine-rich peptide into the pVIII region of the M13KE plasmid. C Utilization of cysteine-rich peptide phage display for the production of SERS substrates. The phage was decorated with an immuno-colloid made of gold-coated magnetic nano-stars (Au-MNS) after treatment with tris (2-carboxyethyl) phosphine hydrochloride solution (TCEP) to activate the thiol groups. The phage was polymerized with silica precursor to give amorphous biomaterial gel and then calcinated to form the mesoporous template. After incubation of the template with a serum sample spiked with sepsis biomarkers, the complexes were separated using a magnet and subjected to Surface-enhanced Raman scattering (SERS) measurement (adopted from [20])

Fig. 6

The structural design of self-assembling chimeric peptide. The peptide sequence comprises hydrophobic and cationic amino acids. The peptide is linked to the hydrophobic alkyl chain to enhance the self-assembly and the hydrophilic PEG unit to provide a stealth effect and improve biocompatibility (adopted from [159])

Fig. 7

A Preparation of anti-ICAM-1-AMPNP to specifically target inflammation sites with overexpressed ICAM-1 receptor. B Preparation of macrophages membrane-coated AMPNP (M−AMPNP) to specifically target bacteria through the TLR2 and TLR4 on the macrophage membrane (Adopted from [22, 160])

Fig. 8

Preparation of Ts-LPs-LEV. Adopted from [165]

Fig. 9

Preparation and evaluation of SS-31 loaded nanoplexes. A The method for fabricating nanoplexes through electrostatic complexation; (B) and (D) DLS characterization; (C) TEM imaging; (E) pH-responsiveness; (F) release patterns at different pHs. (Taken from [181])

Fig. 10

Preparation and in vivo evaluation of γ3-PLGA NPs (A) Preparation of γ3-PLGA NPs loaded with Sparfloxacin and Tacrolimus (B) Effective treatment of lung-infected mice by specific targeting of the overexpressed ICAM-1 (Taken from [188])

Fig. 11

Preparation and mechanism of action of HMPDA@BA/NAD⁺@LSA NPs (A) Preparation of HMPDA@BA/NAD⁺@LSA NPs. B Pharmacological effects of HMPDA@BA/NAD⁺@LSA NPs in an LPS-induced sepsis mice model (Adopted from [191]

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]

Fig. 13

Preparation and characterization of D-/L-GBPs. A Coating of GBPs with D-/L-CF (B) TEM images of peptide-unmodified Au NBPs (C) TEM and (D) SEM images of D-/L-GBPs (adopted from ([194])