Ultrasound-Activated Metal-Organic Frameworks Incorporated Polyacrylonitrile Nanofibers Promote Macrophage...

Macrophage polarization toward the pro-inflammatory M1 phenotype underlies an effective strategy for potentiating antitumor immune responses. Electrical stimulation has emerged as a potent modulator of immune cell polarization. However, conventional electrode-mediated electrical stimulation has limited penetration into deep tissues and relies on external power supplies. Here, we report on ultrasound (US)-responsive piezoelectric nanofibers, constructed by embedding manganese-titanium metal-organic frameworks (MT-MOF) within a polyacrylonitrile (PAN) matrix (MT-MOF/PAN). As a non-centrosymmetric bimetallic framework, MT-MOF generates a heterogeneous charge distribution under mechanical deformation, thereby enhancing the composite's piezoelectric output. Furthermore, interfacial coupling between MT-MOF and the PAN nanofibers provides an additional contribution to this enhancement. Under US stimulation, MT-MOF/PAN nanofibers generates a peak voltage of 0.24 V, substantially exceeding the output of pure PAN nanofibers. In RAW-Blue cells, US-activated MT-MOF/PAN nanofibers significantly activate the nuclear factor-κB (NF-κB) pathway and promote the secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), whereas neither US nor nanofibers alone produce this effect. Mechanistic studies demonstrate that piezoelectric stimulation induces a transient intracellular Ca²⁺ influx, as visualized by Fluo-4 acetoxymethyl ester (Fluo-4 AM) imaging, whereas US alone or nanofibers alone produce no significant effects. These findings establish MT-MOF/PAN nanofibers as a wireless, electrode-free platform for antitumor immunotherapy.