Single-particle combinatorial multiplexed liposome fusion mediated by DNA

Mette Galsgaard Malle, Philipp M.G. Löffler, Søren S.R. Bohr, Magnus Berg Sletfjerding, Nikolaj Alexander Risgaard, Simon Bo Jensen, Min Zhang, Per Hedegård, Stefan Vogel, Nikos S. Hatzakis*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Combinatorial high-throughput methodologies are central for both screening and discovery in synthetic biochemistry and biomedical sciences. They are, however, often reliant on large-scale analyses and thus limited by a long running time and excessive materials cost. We here present a single-particle combinatorial multiplexed liposome fusion mediated by DNA for parallelized multistep and non-deterministic fusion of individual subattolitre nanocontainers. We observed directly the efficient (>93%) and leakage free stochastic fusion sequences for arrays of surface-tethered target liposomes with six freely diffusing populations of cargo liposomes, each functionalized with individual lipidated single-stranded DNA and fluorescently barcoded by a distinct ratio of chromophores. The stochastic fusion resulted in a distinct permutation of fusion sequences for each autonomous nanocontainer. Real-time total internal reflection imaging allowed the direct observation of >16,000 fusions and 566 distinct fusion sequences accurately classified using machine learning. The high-density arrays of surface-tethered target nanocontainers (~42,000 containers per mm2) offers entire combinatorial multiplex screens using only picograms of material. [Figure not available: see fulltext.]

Original languageEnglish
JournalNature Chemistry
Issue number5
Pages (from-to)558-565
Publication statusPublished - May 2022


  • DNA
  • DNA, Single-Stranded
  • Liposomes
  • Membrane Fusion


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