Raman Nanotags-Guided Intraoperative Sentinel Lymph Nodes Precise Location with Minimal Invasion

The accurate positioning of sentinel lymph node (SLN) by tracers during surgery is an important prerequisite for SLN biopsy. A major problem of traditional tracers in SLN biopsy is the short surgery window due to the fast diffusion of tracers through the lymphatics, resulting in a misjudgment between SLN and second echelon lymph node (2^nd LN). Here, a nontoxic Raman nanoparticle tracer, termed gap-enhanced Raman tags (GERTs), for the accurate intraoperative positioning of SLNs with a sufficient surgical time window is designed. In white New Zealand rabbit models, GERTs enable precise identification of SLNs within 10 min, as well as provide the surgeon with a more than 4 h time window to differentiate SLN and 2^nd LN. In addition, the ultrahigh sensitivity of GERTs (detection limit is 0.5 × 10^-12 m) allows detection of labeled SLNs before surgery, thereby providing preoperative positioning information for minimally invasive surgery. Comprehensive biosafety evaluations carried out in the context of the Food and Drug Administration and International Standard Organization demonstrate no significant toxicity of GERTs, which supports a promising clinical translation opportunity of GERTs for precise SLN identification in breast cancer.