Suppression of PARP1 enhances PTEN mRNA therapy in castration-resistant prostate cancer by glycolysis disruption

Current treatments for prostate cancer (PC) inevitably lead to the development of resistance to androgen deprivation therapy, resulting in the emergence of castration-resistant prostate cancer (CRPC), which is currently considered incurable. In this study, we discovered that the loss of phosphatase and tensin homolog (PTEN) function, in combination with elevated poly(ADP-ribose) polymerase 1 (PARP1) expression, significantly shortens the survival of PC patients. Motivated by this finding, we developed an RNA-based therapeutic agent consisting of PARP1-targeting small interfering RNA (siRNA) (siPARP1) and PTEN-expressing mRNA (mPTEN), which were co-encapsulated in an ionizable lipid nanoparticle, named mPsiP@miLAND. Both siPARP1 and mPTEN were shown to individually attenuate tumor cell growth. Moreover, the simultaneous regulation of these two targets nearly completely suppressed proliferation and robustly induced apoptosis and necrosis in CRPC both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, the restoration of PTEN inhibited glycolysis via the PI3K-Akt signaling pathway in CRPC cells, and the silencing of PARP1 further enhanced this effect. Overall, the mPsiP@miLAND developed in this study effectively inhibited the growth of PTEN-deficient prostate tumors, providing a promising strategy to overcome CRPC by exploiting the synergistic effects of PI3K-Akt and PARP inhibition.