Smart Theranostic Nanogels with Swelling‐Driven Contrast for Multimodal Imaging, Sensing, and Photothermal Breast Cancer Ablation

Integrating multimodal imaging and therapeutic functions into a single, stimuli-responsive nanoplatform for minimally invasive cancer therapy remains a major obstacle for theranostic nanomedicines. Most existing nanomedicines fail to sense tumor microenvironment (TME) dynamics, including pH fluctuations, through clinically applicable imaging techniques. These limitations reduce their overall translational potential for personalized therapies. To overcome this challenge, a hybrid nanosystem synergistically integrating carbon nanodots (CDs) and superparamagnetic iron oxide nanoparticles (SPIONs) in a hyaluronic acid network with pH-dependent conformational behavior was developed. While SPIONs are chosen as auxiliary crosslinking agents for their magnetic resonance imaging contrast, CDs display great potential as near-infrared converting nanoheaters capable of inducing localized hyperthermia under the guidance of fluorescence imaging, useful in cancer photothermal ablation. The resulting nanoplatforms, named H-NGs, are capable of actively targeting cancerous cells, penetrating complex 3D multicellular tumor-in-a-dish mammospheres which closely mimic the complex structure of breast cancer. H-NGs enable real-time imaging of TME pH and temperature variations as a consequence of particle-particle distance changes due to swelling/shrinking processes, and act as efficient nanoheaters allowing magnetic resonance and fluorescence imaging-guided photothermal ablation of tumors. These findings significantly advance the field of theranostics integrating minimally invasive cancer therapy with real-time monitoring of the TME.