Dual-responsive stem cell microspheres modified with BDNF for enhanced neural repair in diabetic erectile dysfunction

We previously established an effective method to ameliorate erectile dysfunction (ED) using intracavernous injection (ICI) of mesenchymal stem cell (MSC) microspheres. However, the expression of a key neurotrophic factor, brain-derived neurotrophic factor (BDNF), was low in both MSCs and MSC microspheres, restricting the associated neural repair. Based on the hypoxia and oxidative stress microenvironments within cell spheroids and lesion areas, BDNF-expressing nanocomplexes that are dual-responsive to hypoxia and reactive oxygen species were designed to modify MSCs, achieving high BDNF expression in MSC spheroids. Using the pelvic ganglion as an in vitro model, conditioned medium derived from stimuli-responsive MSC microspheres (SRMs) significantly promoted the growth of axons and alleviated the death of neural and smooth muscle cells. In rats with diabetes-induced ED, SRMs that underwent ICI effectively remained in the penis, demonstrating a potent therapeutic outcome. Penile erectile function, smooth muscle content, and neuropathological changes improved after treatment with SRMs compared to unmodified MSCs.