Pulmonary delivery of gene therapy holds significant clinical potential. While pulmonary administration of naked RNA could induce modest transfection in lung tissues, the underlying transfection mechanisms remain unclear. A hypothesis suggests that the positively charged surfactant protein B (SP-B) may play a significant role in mediating cellular uptake of RNA. Leveraging the advantage of employing an endogenous protein as potential RNA carrier for enhanced biocompatibility and safety, this study aimed to explore the transfection capacity of SP-B by identifying the active regions responsible. The siRNA transfection potential of four peptide fragments strategically derived from SP-B were investigated. SPB-L, the peptide fragment derived from the first 25 amino acids in the N-terminal region, demonstrated significant transfection capacity in A549 human alveolar epithelial cells. Unlike many other reported peptide vectors, transfection efficiency with SPB-L was primarily dependent on peptide concentration with limited correlation to RNA dose. The dependence of peptide concentration on cellular uptake of SPB-L/siRNA complexes was also illustrated in flow cytometry. Overall, these findings support the hypothesis that SP-B can act as an endogenous RNA transfection agent, and that SPB-L represents a promising lead candidate for further optimization.
Chow et al. (2026) studied this question.