Poly(l-lysine)s (PLLs),
and related derivatives, have
received considerable attention as nonviral vectors. High molecular
weight PLLs (H-PLLs) are superior transfectants compared with low
Mw PLLs (L-PLLs), but suggested to be more cytotoxic. Through a pan-integrated
metabolomic approach using Seahorse XF technology, we studied the
impact of PLL size on cellular bioenergetic processes in two human
cell lines. In contrast to L-PLLs (1–5 kDa), H-PLLs (15–30
kDa) were more detrimental to both mitochondrial oxidative phosphorylation
(OXPHOS) and glycolytic activity resulting in considerable intracellular
ATP depletion, thereby initiating necrotic-type cell death. The cellular
differences to polycation sensitivity were further related to the
mitochondrial state, where the impact was substantial on cells with
hyperpolarized mitochondria. These medium-throughput approaches offer
better opportunities for understanding inter-related intracellular
and cell type-dependent processes instigating a bioenergetics crisis,
thus, aiding selection (from available libraries) and improved design
of safer biodegradable polycations for nucleic acid compaction and
cell type-specific delivery
