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Abstract Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Here we report a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, we develop size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. We discover a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery. 

Abstract Hierarchical plasmonic biomaterials constructed from small nanoparticles (NPs) that combine into larger micron‐sized structures exhibit unique properties that can be harnessed for various applications. Using diffusion‐limited aggregation (DLA) and defined peptide sequences, we developed fractal silver biomaterials with a Brownian tree structure. This method avoids complex redox chemistry and allows precise control of interparticle distance and material morphology through peptide design and concentration. Our systematic investigation revealed how peptide charge, length, and sequence impact biomaterial morphology, confirming that peptides act as bridging motifs between particles and induce coalescence. Characterization through spectroscopy and microscopy demonstrated that arginine‐based peptides are optimal for fractal assembly based on both quantitative and qualitative measurements. Additionally, our study of diffusion behavior confirmed the effect of particle size, temperature, and medium viscosity on nanoparticle mobility. This work also provides insights into the facet distribution in silver NPs and their assembly mechanisms, offering potential advancements in the design of materials for medical, environmental, and electronic applications. 

We present a strategy for constructing activatable photoacoustic imaging (PAI) probes for in vivo enzyme activity measurements, based on a dissociation strategy previously applied to in vitro sensing. Unlike conventional nanoparticle aggregation strategies, dissociation minimizes false positives and functions effectively in complex biological environments. Overcoming the challenge of dissociating nanostructure aggregates, which arises from the strong van der Waals forces at short distances, we demonstrate the controlled assembly and dissociation of citrate-capped gold nanorods (AuNRs-citrate) using a diarginine peptide additive and a thiolated polyethylene glycol (HS-PEG-OMe), respectively. This assembly dissociation mechanism enables precise control of the optical and photoacoustic (PA) properties of AuNRs in both in vitro and in vivo settings. Building on these findings, we engineered an enzyme-sensitive PAI probe (AuNRs@RgpB) composed of AuNR assemblies and a PEG-peptide conjugate with a protease-specific cleavage sequence. The probe detects Arg-specific gingipain (RgpB), a protease expressed by Porphyromonas gingivalis associated with periodontal disease and Alzheimer’s disease. Proteolytic cleavage of the peptide sequence triggers AuNR dissociation, resulting in enhanced PA signal output. The probe was designed to be injected intrathecally for preclinical trials to image gingipains and investigate the value of gingipain inhibitors developed for Alzheimer’s disease. The probe’s performance was characterized in vitro using UV−vis spectroscopy and PAI, achieving detection limits of 5 and 20 nM, respectively. In vivo studies involved intracranial injection of AuNRs@ RgpB into RgpB-containing murine models, with PA monitoring over time. RgpB activity produced a four-fold PA signal increase within 2 h, while P. gingivalis-infected mice showed similar signal enhancement. Specificity was confirmed by negligible responses to Fusobacterium nucleatum, a non-RgpB-producing bacterium. Additionally, the system demonstrated utility in drug development by successfully monitoring the inhibition of RgpB activity using RgpB inhibitors (leupeptin and KYT-1) in vivo models. Beyond its immediate application to RgpB detection, this modular approach to plasmonic-based sensing holds significant potential for detecting other proteases, advancing both nanotechnology and protease-targeted diagnostics. 

This review summarizes insights into colorant selection and signal mechanisms for the development of colorimetric sensing and POC sensors. 

A SV3CP-responsive peptide has various performance towards the aggregation of AuNPs with different charge valence. 

This is a correction to the original manuscript. The original manuscript had missing text describing funding sources.