Macrophage-Anchored Nanofibers with Supramolecular Phenolic Gates for pH-Responsive Chemotherapy.

Abstract

Cell-based therapies using macrophages for tumor-targeted drug delivery show great promise, but are hindered by limited drug loading, complex fabrication, and premature payload release. Current hitchhiking strategies often suffer from low cargo retention, nanoparticle endocytosis, and detachment. A universal, simplified system balancing high loading, controlled release, and cellular localization is urgently needed. Here, we report a macrophage-anchored gated nanofibers platform (MAGF) that addresses these challenges via polyphenol-gated electrospun nanofibers. Doxorubicin-loaded PLGA nanofibers are fabricated via electrospinning and coated with a Fe³⁺-tannic acid (TA) supramolecular network, forming a pH-responsive polyphenol gate. This design enables ultra-high drug loading (∼25 wt.%) and minimizes premature leakage under physiological conditions. Importantly, the nanofibers stably adhere to the macrophage surface without internalization, preserving cellular viability, motility, and tumor-homing capacity. Molecular dynamics and density functional theory simulations reveal that strong TA-drug interactions suppress release at neutral pH but dissociate in acidic tumor environments, ensuring site-specific activation. In vivo, MAGF-loaded macrophages demonstrate enhanced drug accumulation in melanoma tumors, significant inhibition of both primary growth and lung metastasis, and favorable biosafety. This work introduces a robust and cell-compatible delivery platform that bridges synthetic nanotechnology with living-cell therapy, offering a generalizable strategy for next-generation, tumor-targeted chemotherapy.