The concept of precision medicine has emerged as a promising way to overcome limitations of standard clinical approaches in the cancer treatment. Engineered theranostic nano-biomaterials combining different therapeutic and diagnostic techniques in a single nanosystem constitute a remarkable strategy to fulfil the promise of personalized precision medicine[1,2]. Near infrared (NIR)-sensitive nanoplatforms simultaneously enabling cancer cells targeting, NIR-induced hyperthermia (43-49 °C) and on demand image-guided drug delivery offer the possibility of activating selective cancer cell death, avoiding undesired side effect and monitoring cancer tissues[3,4]. The combination of chemo- and photothermal therapy (PTT) have gained considerable interest in oncology, since allows overcoming multidrug resistance by inducing the concurrent activation of different pathways of regulated cell death (RCD), such as apoptosis, necroptosis and autophagy . Image-guided photothermal therapy (IG-PTT) allow maximizing anticancer efficacy, but also represents an attractive therapeutic strategy to overcome cancer apoptosis resistance under monitoring [6,7]. Among the nanomaterials useful in IG-PTT (e.g. carbon nanotubes, gold nanoparticles), red-emitting carbon dots (CDs) have shown the most promising combination of optical and delivery properties. CDs have emerged due to their excellent emission in the transparent biological window and photothermal conversion, high biocompatibility and water solubility. In addition, the ultrasmall size of CDs (<5 nm) favours their renal clearance after biodistribution, circumventing toxic effect of bioaccumulation in healthy tissues[8,9].
Herein, we propose a rational synthesis of highly homogeneous biotinylated carbon nanodots (CDs-PEG-BT), with strong red fluorescence and the ability to convert NIR-light into localized heat. The performant optical properties were obtained by bottom-up synthesis, in solvothermal condition and high nitrogen content, of crystalline N-doped CDs, which constitute the carbonaceous core of our systems. CDs-PEG-BT, obtained by surface passivation with biotin-terminated PEG2000 chains, are designed to incorporate high amount of irinotecan (16-28 %) (CDs-PEG-BT@IT) and recognize cancer cells through biotin receptors; acting as NIR-responsive nanoparticles capable of triggering local hyperthermia and massive drug release inside tumor cells. The potential of CDs-PEG-BT@IT in fluorescence imaging (FLI) and chemo-phototherapy was assessed on 2-D models of two different breast cancer cell lines, MDA-MB-231 and MCF-7. In view of their possible precise medicine application, their anticancer efficacy was also evaluated on multicellular 3-D spheroids and patient organoids . The remarkable potential of CDs-PEG-BT@IT as theranostic anticancer nanosystem was confirmed by RGD expression analysis, which demonstrated their high biocompatibility and revealed on-demand photothermal activation of necroptosis pathway. The NIR-triggered drug release combined with local hyperthermia induced the concurrent activation of necroptosis and apoptosis, TNFα and RIPK1 mediate constituting an efficient anticancer strategy in refractory breast cancer treatment, reinforcing the potential of these theranostic nanosystems for image-guided photothermal (IG-PTT) applications.