Reduction of tumor burden via precise photothermal release of sirolimus by carbon nanodots in 3D plexiform neurofibroma-in-a-dish models

Plexiform neurofibromas (PNs) are benign but complex tumors associated with neurofibromatosis type 1 (NF1), often making surgery difficult due to hypervascularization. PNs may progress to malignant tumors, increasing mortality risks, especially in adolescence and adulthood. Personalized therapies, such as chemo-photothermal image-guided treatments, provide targeted, less invasive options, improving efficacy where surgery is not viable. Carbon nanodots (CDs) with red-to-near-infrared fluorescence and efficient photothermal conversion in the biologically transparent window (750–1100 nm) show promise as theranostic tools, enabling localized heating of cancer cells under imaging guidance. CDs can also combine photothermal therapy with light-triggered, on-demand drug release due to their large surface area and zero-dimensional size. In this study, we developed a drug-loaded CDs-based nanoplatform with a narrow size distribution (8.3 ± 0.6 nm) that is optically and colloidally stable, functionalized with biotin-PEG chains via a copper(I)-catalyzed click reaction. This CDs-PEG-BT conjugate consists of an N-doped graphitic core (∼ 2 nm) functionalized with PEG2k chains bearing biotin, serving as a colloidal stabilizer and tumor-targeting agent. Additionally, the PEG shell was loaded with sirolimus (5 % w/w), a water-insoluble and unstable mTOR inhibitor effective against PNs. The drug was released in a near-infrared-sensitive manner, allowing controlled, localized release upon laser stimulation. The potential of the CDs-PEG-BT@Sir conjugate for fluorescence imaging and chemo-photothermal therapy was demonstrated both in vitro and in 3D PN-in-a-dish models, simulating the complex tumor microenvironment. The CDs-PEG-BT@Sir platform offers high colloidal and fluorescence stability, effective photothermal conversion, and selective tumor targeting, showing strong potential as a theranostic agent for precision NF1 treatment.