Overcoming the blood-brain barrier: the role of functionalized carbon dots in treating central nervous system diseases.

Central nervous system diseases (CNSDs) pose a significant therapeutic challenge, largely due to the restrictive blood-brain barrier (BBB). While nanocarriers like liposomes, polymeric nanoparticles, and exosomes have been explored for brain delivery, carbon dots (CDs) have emerged as a particularly promising platform. These carbon-based nanomaterials offer advantages such as small size, excellent biocompatibility, and versatile surface chemistry, enabling precise functionalization. Compared to liposomes and polymer nanoparticles, CDs exhibit superior size uniformity, photophysical properties, and chemical stability. Unlike exosomes, they are synthetically controllable, scalable for mass production, and amenable to precise surface modification. A key advantage lies in their ability to cross the BBB via specific molecular mechanisms, such as receptor‑mediated transcytosis, when conjugated with targeting ligands (e.g., transferrin, lactoferrin, or cell‑penetrating peptides). This allows for disease-specific targeting, for instance, of amyloid-β plaques in Alzheimer's or overexpressed receptors in brain tumors. CDs can serve as intrinsic therapeutics or as drug carriers. However, their clinical translation depends on addressing critical issues of long-term safety, potential neurotoxicity (such as inducing oxidative stress and inflammation), and biodegradability. This review systematically summarizes the synthesis methods and functionalization strategies of CDs, alongside the molecular mechanisms underlying their BBB penetration. It focuses on their therapeutic potential for CNSDs, providing a comparative analysis with other common nanocarriers. Furthermore, it evaluates the current research and improvement strategies concerning CDs toxicity, biocompatibility, and long-term safety. Finally, the review outlines ongoing challenges and future directions for the field.