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Optimizing drug loading is crucial for enhancing therapeutic efficacy and safety, as higher loading allows for lower LNP doses, reducing overall nanomaterial burden. Addressing this knowledge gap is essential for advancing LNP\u2010based cancer therapies. This study integrates DNA barcoding technology with LNPs to evaluate their in vivo delivery behaviors under varying drug loadings. Using a sequential nanoprecipitation method, DNA\u2010barcoded LNPs with low (1%), medium (16%), and high (26%) drug loadings are fabricated, each tagged with a unique DNA barcode for precise tracking. Pooled LNPs are intravenously administered to tumor\u2010bearing mice, and their biodistribution across organs is quantified via qPCR. High drug\u2010loading LNPs demonstrate preferential accumulation in the spleen, while low drug\u2010loading LNPs exhibit higher liver accumulation, suggesting faster clearance. Cellular uptake analysis reveals enhanced uptake of high drug\u2010loading LNPs by tumor\u2010associated macrophages within the tumor microenvironment (TME). This study establishes a robust platform for simultaneous and high\u2010sensitivity monitoring of LNP behaviors, significantly reducing animal use and interanimal variability. The findings guide the rational design for developing optimal LNPs for cancer therapies targeting specific TME components.<\/jats:p>","DOI":"10.1002\/adhm.202501914","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T03:46:02Z","timestamp":1750909562000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["DNA Barcoding\u2010Enabled Tracking of Lipid Nanoparticles: Drug\u2010Loading\u2010Dependent Biodistribution and Tumor Microenvironment Targeting"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0449-8382","authenticated-orcid":false,"given":"Letao","family":"Xu","sequence":"first","affiliation":[{"name":"School of Chemical Engineering Faculty of Science Engineering and Technology The University of Adelaide  Adelaide SA 5005 Australia"},{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland  St Lucia QLD 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