Xylem-inspired anisotropic porous silk microneedles enable efficient interstitial fluid sampling for local biomarker and proteomic profiling of skin diseases.

Chronic inflammatory skin diseases require safe and repeatable access to localized molecular information to enable mechanistic studies and precision management, yet existing sampling methods remain invasive or poorly representative of the skin microenvironment. Here, we develop xylem-inspired anisotropic porous silk microneedle (APSMNs)for rapid, high-yield, and minimally invasive sampling of skin interstitial fluid (ISF). By integrating directional cryo-templating, ice-templated solvent-exchange crosslinking, and Hofmeister effect-induced salting-out, APSMNs feature vertically aligned microchannels and high mechanical robustness, ensuring reliable skin penetration and swelling-independent ISF uptake. A single patch collects >10 μL ISF within 5 min, supports transport of macromolecules of at least 150 kDa, and achieves recovery efficiencies above 95%, yielding >180 μg total protein from mouse skin. In psoriasis-like mice, APSMN-collected ISF enables ELISA quantification of inflammatory biomarkers with sensitivity higher than serum and comparable to skin biopsy. Proteomic analysis identifies >6300 proteins in APSMN-collected ISF, exceeding serum and approaching skin biopsy, with significantly more upregulated proteins (2.89- and 2.54-fold increase compared with serum and biopsy, respectively). These findings demonstrate APSMNs as a robust platform for minimally invasive ISF sampling, enabling biomarker quantification and proteomic analysis. It supports longitudinal monitoring and discovery of disease-relevant molecular signatures in skin disorders.