A versatile platform based on matrix metalloproteinase-sensitive peptides for novel diagnostic and therapeutic strategies in arthritis

Abstract

Matrix metalloproteinases (MMPs), coupled with other proteinases and glycanases, can degrade proteoglycans, collagens, and other extracellular matrix (ECM) components in inflammatory and non-inflammatory arthritis, making them important pathogenic molecules and ideal disease indicators and pharmaceutical intervention triggers. For MMP responsiveness, MMP-sensitive peptides (MSPs) are among the most easily synthesized and cost-effective substrates, with free terminal amine and/or carboxyl groups extensively employed in multiple designs. We hereby provide a comprehensive review over the mechanisms and advances in MSP applications for the management of arthritis. These applications include early and precise diagnosis of MMP activity via fluorescence probe technologies; acting as nanodrug carriers to enable on-demand drug release triggered by pathological microenvironments; and facilitating cartilage engineering through MMP-mediated degradation, which promotes cell migration, matrix synthesis, and tissue integration. Specifically, the ultra-sensitive MSP diagnostic probes could significantly advance the early diagnosis and detection of osteoarthritis (OA), while MSP-based drug carriers for rheumatoid arthritis (RA) can intelligently release anti-inflammatory drugs effectively during flare-ups, or even before symptoms manifest. The continuous progress in MSP development may acceleratedly lead to novel management regimens for arthropathy in the future.

Fig. 1

The Multifaceted Role of MSPs in the Management of Arthritis. The primary applications of MSPs in arthritis can be categorized into three types: accurate early diagnosis, disease-responsive drug delivery, and biomaterial-based repair. Abbreviations: FRET, Förster resonance energy transfer; AIEgen, aggregation-induced emission fluorogen; MSPs, MMP-sensitive peptides.

Fig. 2

A Sankey diagram depicting research on MSP in arthritis.

Fig. 3

Strategies for Constructing Diagnostic Probes by Integrating MSPs into Molecules with Different Luminescent Mechanisms. 1. A pair of FRET chromophores conjugated to the two ends of the MSPs releases a fluorescence signal when MMP cleaves the peptide and separates the chromophores. 2. Cleavage of MSPs leads to the aggregation of hydrophobic AIEgen residues, activating a fluorescent signal. 3. Cleavage of MSPs results in the washout of the fluorescent group, leading to a decrease in fluorescence intensity. Abbreviations: FRET, Förster resonance energy transfer; AIEgen, aggregation-induced emission fluorogen; MSPs, MMP-sensitive peptides.

Fig. 4

MMP-Sensitive Drug Delivery in Arthritis. 1. Nano drugs were modified with guiding molecules containing an MSP spacer to achieve hierarchical targeting. 2. Drugs loaded in MSP-crosslinked hydrogels were released upon degradation of the hydrogel by MMPs. 3. Hydrogels, lipid nanoparticles, and nanoparticle-hydrogel composites assembled from TG-18 have the ability to release the loaded drug in response to MMP activity based on the cleavable ester bond of TG-18.

Fig. 5

Construction of Various MSP-Based Scaffolds. The most common crosslinking mechanism employed in MSP-based scaffolds involves the reaction between thiol groups (usually on cysteine) and double bonds (on Vinyl sulfone, Vinyl, Maleimide, Acrylate, or Norbornene), or the reaction between two double bonds. The strategies for achieving MMP sensitivity can be highly flexible, with MSPs acting as crosslinkers, backbones, or both.

Fig. 6

Novel MSP-based Scaffolds with Multiple Functions. Multifunctional MSP scaffolds have been thoroughly investigated, encompassing the integration of additives, bioactive matrices, advancements in crosslinking methodologies, and the incorporation of novel fabrication techniques. HA, hyaluronic Acid; TG, transglutaminase.