Carrier-free procyanidin-ferric nanonetworks loading gefitinib to inhibit TMEM16A-EGFR mutual activation loop for photothermally enhanced breast cancer targeted therapy

The calcium-activated chloride channel TMEM16A is frequently overexpressed in breast cancer, establishing a reciprocal activation loop with EGFR signaling pathways that play a crucial role in the proliferation of breast cancer. Consequently, the simultaneous targeting of TMEM16A and EGFR may be a promising, yet underexplored, therapeutic strategy for breast cancer. Herein, we developed a carrier-free polyphenol nanonetwork (PFGH) using procyanidin (PC), a natural polyphenolic TMEM16A inhibitor, via coordination with Fe³⁺, for co-delivering PC and gefitinib (Gef), an EGFR inhibitor. The resulting nanosystem, eliminating the requirement for additional nanocarriers, exhibited remarkable photothermal properties, pH-responsive drug release, and CD44-mediated tumor targeting. Functional assays confirmed that PFGH, under NIR irradiation, potently inhibited TMEM16A channel currents and exhibited superior antiproliferative effects compared to free PC, Gef, or their combination. RNA sequencing analysis confirmed the transcriptomic alterations in apoptosis, cell proliferation, and cancer-related pathways induced by the PFGH. <i>In vivo</i> studies further demonstrated that PFGH augments tumor-targeted combinatorial therapy, leveraging its photothermal properties, targeted co-delivery, and loop-suppressing activity. For the first time, our work presents a carrier-free polyphenol nanonetwork specifically engineered to co-target the TMEM16A-EGFR mutual activation loop, offering a novel, synergistic therapeutic approach for breast cancer.