The reverse transfection approach represents a critical methodological adaptation for senescent cells that overcomes the fundamental barriers these cells pose to standard transfection methods. Unlike forward transfection, where cells are pre-plated and allowed to adhere before adding transfection complexes, reverse transfection involves adding cells in suspension directly onto pre-formed hTERT mRNA-lipid complexes. This technique dramatically increases transfection efficiency in senescent cells by maximizing exposure to transfection complexes during the critical attachment phase, when membrane remodeling is most active.
The protocol’s core conceptual shift is to treat senescent cells as a distinct delivery problem, not as just hard‑to‑transfect versions of young cells. In senescence, global changes in membrane lipid composition, including phospholipids, sphingolipids, and cholesterol, alter membrane fluidity, curvature, and protein-lipid interactions, while contributing to the senescence-associated secretory phenotype1,2,3. Senescent cells also exhibit reduced clathrin- and caveolae-mediated receptor endocytosis and altered endocytic routing, driven in part by down‑regulation of amphiphysin‑1 and compensatory changes in caveolin expression, which blunt receptor-mediated uptake and signaling4,5,6. In parallel, the Rab7-regulated late endosome-lysosome axis and the broader endosomal-autophagic-lysosomal (EAL) network become dysregulated, with Rab7 acting as a master controller of endolysosomal maturation and autophagosome-lysosome fusion, which are perturbed in aging and neurodegeneration7.
Senescent cells commonly upregulate multiple components of the lysosomal processing and adaptation system (LYPAS), including TFEB/TFE3-driven lysosomal biogenesis and chaperone-mediated autophagy, thereby increasing lysosomal mass. However, individual lysosomes frequently exhibit elevated luminal pH, membrane damage, and altered proteolytic capacity, contributing to lysosomal dysfunction despite their increased abundance8,9,10,11. Collectively, these changes can channel internalized material more efficiently into degradative endolysosomal compartments, increasing the likelihood that delivered RNA or protein will be degraded before productive cytosolic release9,10,11. Reverse transfection directly targets the earliest window when membranes are remodeling, during adhesion, forcing sustained, high‑avidity contact between cells and mRNA-lipid complexes and at least partly bypassing impaired steady‑state endocytosis in fully adherent senescent cells4,5,6,12.
On the RNA design side, the protocol assumes that in an aging context, a simple cap + tail baseline is insufficient: full nucleoside modification (for example, pseudouridine or N1‑methylpseudouridine plus 5‑methylcytidine) is treated as non‑negotiable to decouple translation from endosomal Toll‑like receptor sensing and type I interferon induction. Foundational work showed that incorporation of modified nucleosides into RNA suppresses activation of TLR3, TLR7, and TLR8 and markedly reduces dendritic cell cytokine production, providing a mechanistic basis for the reduced innate immunogenicity of current nucleoside‑modified mRNA platforms13. More recent reviews of mRNA–LNP vaccines and mRNA medicines emphasize the coordinated engineering of the 5′ cap, UTRs, coding sequence, and poly(A) tail to increase stability and translation in vivo while minimizing innate immune activation14. In particular, poly(A) tail length and architecture have emerged as key determinants of in vitro transcribed mRNA stability and translational output, motivating extended or engineered poly(A) designs in therapeutic mRNA15.
Layered onto this, the protocol explicitly builds in protection against extracellular and endosomal RNases during complex formation and uptake, together with a defined endosomal‑escape window using a transient lysosomotropic agent such as chloroquine16,17. Chloroquine has long been used as a functional probe of endosomal barriers and can markedly increase target engagement and silencing by siRNA or antisense oligonucleotides by promoting endosomal membrane disruption and escape of nucleic acid cargo into the cytosol18. At the same time, live‑cell and super‑resolution imaging of LNP‑delivered mRNA have demonstrated that productive delivery is tightly bottlenecked at rare escape events from early/recycling endosomes, rather than by initial uptake per se, underscoring the importance of deliberately engineering an endosomal‑escape step for mRNA therapeutics19.
Collectively, these senescence-associated alterations in membrane dynamics, endocytic trafficking, lysosomal processing, and innate immune activation create substantial barriers to efficient mRNA delivery. The reverse-transfection strategy described here was developed to address these limitations by combining optimized mRNA engineering, RNase protection, enhanced endosomal escape, and direct exposure of attaching cells to preformed mRNA-lipid complexes. Although hTERT mRNA is used as the model cargo, the workflow is broadly applicable to the delivery of other large therapeutic mRNA transcripts into senescent and difficult-to-transfect cell populations20,21,22.