Predominance of the Noncell-Mediated Migration Mechanism for Large Nanoparticles into Sentinel Lymph Nodes

Efficient nanoparticle migration to sentinel lymph nodes (SLNs) is vital for immunotherapy and diagnostics, yet the governing mechanisms remain controversial. Current paradigms assume a 100 nm size cutoff, where larger nanoparticles rely exclusively on slow, cell-mediated transport rather than rapid noncell-mediated migration, including diffusion and convection. Here, we reveal a predominant noncell-mediated delivery mechanism using 120 nm gold particles as a model. We adopt a multiscale correlative imaging approach, integrating Raman imaging, optical microscopy, and electron microscopy, to quantify in vivo transport pathways. Unexpectedly, the noncell-mediated pathway accounts for approximately 82% of nanoparticle migration to the SLN, while cell-mediated delivery contributes only 18%. Upon entry into the SLNs, particles are rapidly internalized by resident macrophages for prolonged retention. This work helps to refine the fundamental framework of lymphatic trafficking, providing insights into the design of vaccines and lymph node-targeted therapeutics.