# A Multifunctional Peptide Linker Stably Anchors to Silica Spicules and Enables MMP-Responsive Release of Diverse Bioactive Cargos

## TL;DR

A new peptide linker binds strongly to silica spicules and releases bioactive substances in response to enzymes, enabling controlled drug delivery through natural skin channels.

## Contribution

A peptide linker that combines strong silica binding with matrix metalloprotease (MMP)-responsive release of diverse bioactive cargos.

## Key findings

- The lead peptide P176 showed high silica affinity and robust biophysical signals.
- MMP-responsive cleavage achieved >90% payload release within 60 minutes.
- The peptide enabled controlled delivery of Vitamin C and Stigmasterol with minimal leakage.

## Abstract

Silica spicules provide a natural transdermal conduit but require a linker that binds strongly under physiological conditions and releases payloads selectively in response to biological cues. Existing silane chemistries or polydopamine coatings lack enzyme responsiveness and show limited control over release. We created a 180-member peptide library with the motif L–X1–X2–[Y–F–Y]–A–L–G–P–H–C and screened for silica binding. Biophysical assays (circular dichroism, ζ-potential, quartz crystal microbalance, atomic force microscopy) and molecular dynamics identified high-affinity binders. The lead, P176, was tested for matrix metalloprotease (MMP)-responsive cleavage. Conjugation and release of Vitamin C and Stigmasterol were analyzed by HPLC and Franz diffusion cells. P176 showed high silica affinity (~55 µg mg−1), robust biophysical signals (Δf −35 to −38 Hz; rupture force ~154 pN; ζ shift −22 to−11.5 mV), and favorable adsorption energy (−48.5 kcal mol−1, contact 4.5 nm2, 8.5 H-bonds). The MMP gate displayed efficient kinetics (Vmax 117.9 RFU·min−1, Km 5.0 µM) with >90% cleavage at 60 min, reduced to 26% by inhibitor. Conjugation yields reached 87% (Vitamin C) and 77% (Stigmasterol). Franz diffusion showed MMP-dependent release (24 h: Vitamin C 90–96%, Stigmasterol 80–85%) with minimal basal leakage. Released Vitamin C enhanced collagen I to ~250% in fibroblasts, while Stigmasterol attenuated LPS-induced macrophage morphology; keratinocytes retained normal marker expression. This study demonstrates that a single amphipathic, sequence-programmed peptide can couple strong silica anchoring with protease-responsive release and broad payload compatibility, establishing a versatile platform for spicule-based transdermal and regenerative delivery.