pH-tuned ionizable lipids enable cytosolic delivery of siRNA in orthotopic tumour models
Summary
A systematic screen of 42 ionizable lipid structures identifies a pKa window between 6.2 and 6.6 that maximises endosomal escape without compromising circulation stability.
Endosomal escape remains the dominant bottleneck in non-viral nucleic acid delivery: the majority of internalised cargo is degraded before it reaches the cytosol.
We synthesised a library of 42 ionizable lipids varying the linker chemistry, the number of unsaturated tails and the headgroup pKa, then measured both apparent pKa and functional knockdown in orthotopic tumour models.
The screen converged on a narrow pKa window of 6.2 to 6.6. Formulations in this range achieved 4.1-fold higher cytosolic siRNA concentration than the reference standard, with no increase in hepatic toxicity markers.
Critically, the optimum was not transferable across cell lines without adjusting PEG shedding kinetics — a result that argues against one-size-fits-all formulation platforms.
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