Alkaline Phosphatase-Responsive Composite Hydrogels Modulating Tumor Mechanical Properties for Cervical Cancer Therapy

Abstract Alkaline phosphatase (ALP) is aberrantly overexpressed in cervical tumor cells, particularly HeLa cells, rendering it a promising endogenous trigger for tumor therapeutic interventions. Herein, a thiol-functionalized ALP-responsive peptide (pY) was integrated with gold nanoparticles (Au NPs) via Au–S bonds to fabricate the composite hydrogel precursor (Au-pY). Upon catalysis by tumor-overexpressed ALP, Au-pY self-assembles into Au NP-embedded composite hydrogels (Au-Gel) both intracellularly and extracellularly. Au-Gel exhibits enhanced mechanical properties compared to pure peptide hydrogels. It acts as an extracellular physical barrier and upregulates Lamin A/C, a key protein associated with nuclear stiffness. This in turn disrupts actin cytoskeleton dynamics and suppresses the migration and invasion of HeLa cells, promoting cell apoptosis. Furthermore, Au-Gel-mediated photothermal therapy, triggered by near-infrared irradiation, potentiated the cytotoxicity against HeLa cells and facilitated cell apoptosis/necrosis. Further in vivo investigations demonstrated that Au-Gel effectively inhibits both cervical tumor growth and lung metastasis in a HeLa cell xenograft nude mouse model. Our findings underscore the promising application of Au-Gel in cervical cancer therapy, providing novel insights and strategies into multipronged approaches to combat cervical cancer.