Deep tumor penetration of supramolecular Fmoc-Glyco/ Fmoc-diphenylalanine-DOX drug loaded nanorods for targeted chemotherapy

Nanoparticles (NPs) have been extensively investigated in modern cancer chemotherapy for their advantages in targeted drug delivery, enhanced efficacy and reduced toxicity. However, clinical evidence continues to indicate modest therapeutic efficacy of these nanomedicines, largely attributed to insufficient drug accumulation and poor tissue penetration in tumors. In the current study, we discovered that synergetic and precise control over nanoparticle shape and surface functionalization improves tumor penetration and enhances chemotherapy outcomes. Specifically, supramolecular nanospheres/nanorods self-assembled from scaffolding Fmoc-FF, hepatocyte targeting Fmoc-monosaccharides and the anti-tumor drug doxorubicin (DOX) have been associated via the synergetic control of their nanostructured morphologies and the surface presentation of bioactive signals. These pH-sensitive self-assembled nanoparticles enable controlled nanostructure shape and multivalent carbohydrate-functionalized surfaces, allowing activation in the acidic tumor microenvironment for triggered drug release. In vitro experiments demonstrated that the galactose-modified nanorod FGal 1–2 , measuring approximately 250 nm in length and of 25 nm in diameter, displayed the highest toxicity towards HepG2 cells and significantly enhanced cellular uptake. Additionally, nanorod FGal 1–2 demonstrated the deepest penetration (> 80 μm) in a 3D tumor spheroid model, surpassing the nanosphere FGal 1–1 and longer nanorod FGal 1–3 . Moreover, in vivo animal studies further revealed higher tumor accumulation of nanorod FGal 1–2 compared to the corresponding nanosphere, along with the strongest tumor inhibition, markedly reduced cardiotoxicity of DOX, and an 85% reduction in tumor volume. This work offers new insights into the design of nanoparticles with functional/morphological effects in their properties for advanced anti-tumor drug delivery.