miRNA delivery via nanowires restores functional responses in aged T cells

Aging reshapes CD8+ T cell immunity by depleting naive populations, narrowing repertoire diversity, and promoting dysfunctional states, thereby weakening responses to infection or vaccination. This study presents a polyethyleneimine (PEI)-functionalized silicon nanowire platform for high-viability, non-viral delivery of single or multiplexed microRNAs (miRNAs) into resting aged CD8+ T cells. Nanowires enable transient modulation of transcriptional programs governing T cell activation, metabolism, proliferation, and differentiation. Delivering a single miRNA influences early activation and differentiation stages, while multiplexed miRNA delivery leads to a broader boost in activation responses, effector functions, metabolic health, and cell proliferation. In vivo, ex vivo-treated aged CD8+ T cells exhibit enhanced early effector priming following antigen exposure. Similarly, in aged human CD8+ T cells, multiplexed miRNA enhances activation and cytotoxic responses and sustains an effector-primed state during early activation and expansion. This method consistently improves function across donors aged from healthy individuals to those with current or past cancer.