Self-Amplifying Assembly of Peptides in Macrophages for Enhanced Inflammatory Treatment

Abstract

Enzyme-regulated in situ self-assembly of peptides represents one versatile strategy in the creation of theranostic agents, which, however, is limited by the strong dependence on enzyme overexpression. Herein, we reported the self-amplifying assembly of peptides precisely in macrophages associated with enzyme expression for improving the anti-inflammatory efficacy of conventional drugs. The self-amplifying assembling system was created via coassembling an enzyme-responsive peptide with its derivative functionalized with a protein ligand. Reduction of the peptides by the enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) led to the formation of nanofibers with high affinity to the protein, thereby facilitating NQO1 expression. The improved NQO1 level conversely promoted the assembly of the peptides into nanofibers, thus establishing an amplifying relationship between the peptide assembly and the NQO1 expression in macrophages. Utilization of the amplifying assembling system as vehicles for drug dexamethasone allowed for its passive targeting delivery to acute injured lungs. Both in vitro and in vivo studies confirmed the capability of the self-amplifying assembling system to enhance the anti-inflammatory efficacy of dexamethasone via simultaneous alleviation of the reactive oxygen species side effect and downregulation of proinflammatory cytokines. Our findings demonstrate the manipulation of the assembly of peptides in living cells with a regular enzyme level via a self-amplification process, thus providing a unique strategy for the creation of supramolecular theranostic agents in living cells.

Intracellular Enzyme-Instructed Self-Assembly of Peptides (IEISAP) for Biomedical Applications

“…Although circumscribed inflammation is beneficial for human health, excessive or persistent inflammation causes allergies, autoimmune diseases, asthma, and sepsis, which are the major causes of illness and death. IEISAP has been implemented to improve the efficacy of a traditional antiinflammatory drug dexamethasone (DEX) by increasing its cellular uptake and retention and prolonging drug release [ 120 ], or decreasing its ROS-caused side effects [ 121 ]. For example, Song et al reported the self-amplifying assembly of peptides in response to the expression of the enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) in inflamed macrophages for improving the efficacy of DEX ( Figure 9 ) [ 121 ].…”

“…IEISAP has been implemented to improve the efficacy of a traditional antiinflammatory drug dexamethasone (DEX) by increasing its cellular uptake and retention and prolonging drug release [ 120 ], or decreasing its ROS-caused side effects [ 121 ]. For example, Song et al reported the self-amplifying assembly of peptides in response to the expression of the enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) in inflamed macrophages for improving the efficacy of DEX ( Figure 9 ) [ 121 ]. The authors coassembled a quinone propionic acid (QPA)-linked pentapeptide AmpFQ and its derivative (AmpFQ−ETGE), containing an ETGE sequence from the nuclear factor erythroid 2-related factor 2 (Nrf2) domain, leading to the formation of AmpFQB nanoparticles.…”

“… Schematic presentation showing the NQO1-responsive self-amplifying assembly of peptides in macrophages. Reprinted/adapted with permission from [ 121 ]. Copyright 2022, American Chemical Society.…”

Surfactant-Assisted Assembly of Dipeptide Forming a Broom-like Structure

“…Natural and spontaneous self-organized amyloid fibril assemblies have encouraged the study of peptides as bio-supramolecular structural building blocks [ 1 , 2 , 3 ]. The behavior of peptides, which can self-assemble into various nanostructures, has attracted much attention because of their applications in biomedical, bioengineering and drug production [ 4 , 5 , 6 , 7 , 8 ]. In contrast to other supramolecular structural motifs, the unique and desirable features of peptides include their chemical diversity, sequence-specific secondary structures, biomolecular recognition, high biocompatibility, and ease of synthesis [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Light-Triggered Self-Assembly of Peptide Nanoparticles into Nanofibers in Living Cells through Molecular Conformation Changes and H-Bond Interactions

“…Inspired by nature, many artificial self-assembled peptide-based materials have been developed in recent years. , Morphology modulation of peptide-based self-assembly under specific conditions has been emerging as a versatile strategy in controlling cellular behaviors . One of the most commonly used methods for controlling self-assembly is to utilize the selective catalytic activity of biomarkers (e.g., enzyme, pH, and temperature). − Ideally, the designed peptides should respond to subtle changes in the physiological conditions of the targeted physiological conditions. Yet, such endogenous-dependent strategies are usually limited to physiological conditions where there is a significant difference between normal and tumor tissue.…”