Y. Zhu, Y. Miao, I. J. Anderson, Y. Li, B. Aghnatios, J. No, J. Ma, D. Yu, C. Wei, X. Lu, J. Wang, J. van de Klashorst, H.-Q. Mao, J. W. Hickey
Existing pooled lipid nanoparticle (LNP) screens lack spatial information on formulation localization, cellular uptake, and associated multicellular tissue responses. Here we introduce NanoSTAMP, a spatially resolved, pooled in vivo screening platform for barcoded LNP libraries that uses fluorescence in situ hybridization (FISH)-based barcode readout and is compatible with spatial omics. NanoSTAMP links LNP formulation to cell-type specific uptake, cargo expression, and nearby multicellular neighborhoods within intact tissue, which enables spatially-informed design of RNA delivery, establishing tissue architecture as a dimension of LNP performance.