Topology- and sequence-controlled β-amyloid recognition by a KLVFF/transferrin-functionalized csq porphyrinic zirconium MOF (PCN-222).

Abstract

Recognition of amyloid-β (Aβ) by structurally defined inorganic scaffolds offers a route to dissecting how framework geometry and surface chemistry govern peptide-material interactions. We report transferrin (Tf)/KLVFF-PCN-222, a bioinorganic recognition platform built by covalently co-grafting the Aβ-homologous pentapeptide KLVFF and transferrin (Tf) onto the csq-topology porphyrinic zirconium MOF PCN-222 via EDC/NHS chemistry. The one-dimensional hexagonal mesopore channels (∼3.7 nm) and the dense meso-tetrakis (4-carboxyphenyl)porphyrin (TCPP) sites of the csq framework provide geometric access for Aβ1-42 monomer diffusion and an array of peptide-porphyrin recognition contacts. Fluorescence quenching and isothermal titration calorimetry returned an apparent dissociation constant (K _d,app) of 33.5 ± 4.2 nM for the Aβ1-42 monomer (apparent fluorescence-mode limit of detection (LOD) = 1.8 nM), and circular dichroism showed that the probe suppressed Aβ β-sheet conversion (14% vs. 41% β-sheet content at 24 h). A panel of structural controls-scrambled FFKLV, the narrow-pore fcu MOF UiO-66-NH₂, and the TCPP-based ftw MOF-525-together with a selectivity screen against BSA, IgG, Tau, α-synuclein, and lysozyme (selectivity ratio >12 for Aβ1-42) indicates that KLVFF sequence specificity and csq mesopore geometry act cooperatively to drive recognition. The framework retains an intrinsic NIR photothermal property (photothermal conversion efficiency, η = 47.3 ± 1.8% at 808 nm); the photoacoustic measurement reported here is a probe concentration calibration only, and no Aβ-responsive photoacoustic signal was established. In an hCMEC/D3 in vitro monolayer, the apparent permeability coefficient (P _app) reached 1.78 × 10^-5 cm s^-1 with ∼48% of the flux being TfR1-competition-sensitive, and SH-SY5Y viability was partially preserved in a tandem BBB-neuron Transwell model. All validations are in vitro. This work provides a topology-controlled, structure-function proof of concept for csq Zr-TCPP frameworks as bioinorganic platforms for Aβ recognition and conformational modulation.