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 (Kd,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 (Papp) 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.