Highly Homogeneous Biotinylated Carbon Nanodots: Red-Emitting Nanoheaters as Theranostic Agents toward Precision Cancer Medicine.

Very recent red-emissive carbon nanodots (CDs) have shown potential as near-infrared converting tools to produce local heat useful in cancer theranostics. Besides, CDs seem very appealing for clinical applications combining hyperthermia, imaging, and drug delivery in a single platform capable of selectively targeting cancer cells. However, CDs still suffer from dramatic dot-to-dot variability issues such that a rational design of their structural, optical, and chemical characteristics for medical applications has been impossible so far. Herein, we report for the first time a simple and highly controllable layer-by-layer synthesis of biotin-decorated CDs with monodisperse size distribution, well established polymeric shell thickness, and degree of surface functionalization, endowed with strong red luminescence and the ability to convert NIR light into heat. These CDs, henceforth named CDs-PEG-BT, consist of a carbonaceous core passivated with biotin-terminated PEG2000 chains, which we demonstrate as active targeting groups to recognize cancer cells. The CDs-PEG-BT are designed to efficiently incorporate a high amount of anticancer drugs such as irinotecan (16-28%) and to act as NIR-activated nanoheaters capable of triggering local hyperthermia and massive drug release inside tumors, thus provoking sudden and efficient tumor death. The potential of the irinotecan-loaded CDs-PEG-BT (CDs-PEG-BT@IT) in fluorescence imaging was studied on 2D cultures and on complex 3D spheroids mimicking in vivo tumor architectures, showing their capability of selectively entering cancer cells through biotin receptors overexpressed in cell membranes. The efficient anticancer effect of these CDs was thoroughly assessed on multicellular 3D spheroids and patient organoids (tumor-on-a-dish preclinical models) to predict the drug response in humans in view of personalized medicine applications. CDs-PEG-BT@IT have a smart combination of properties, which pave the way to their real-world use as anticancer theranostic agents for image-guided photothermal applications.