Self-assembly GSH response based Buforin IIb-Olaparib nanocombination synergistically promotes DNA damage for prostate cancer immunotherapy

Cancer demonstrates an extreme resistance to induced DNA damage, resulting in treatment failure, recurrence, and unfavourable prognosis. This work found Buforin IIb peptide and the poly(ADP-ribose) polymerase (PARP) inhibitor Olaparib (OLA) as a novel combination that synergistically induces DNA damage and elicits immu nogenic cell death (ICD) in a prostate cancer model. Consequently, this research developed an amphiphilic prodrug connected by a disulfide bond between the EGFR-targeting peptide (GE11) and the DNA affinity-toxic peptide (Buforin IIb). This amphiphilic prodrug can self-assemble into micelles (GPBF@OLA), encapsulating OLA within its hydrophobic core and releasing Buforin IIb and OLA through a GSH-responsive mechanism. The released Buforin IIb peptide can induce DNA damage and activate the DNA damage response (DDR) pathway, while OLA exacerbates the accumulation of DNA damage by inhibiting PARP activity. In the RM-1 prostate cancer model, GPBF@OLA demonstrated selective targeting, enhanced DNA damage, promoted CD8+ T cell infiltration, and boosted anti-cancer efficacy. Furthermore, in the RM-1 renal metastasis model, GPBF@OLA effectively suppressed tumor metastasis. By integrating a DNA damage repair inhibitor with a tumor cytotoxic peptide, GPBF@OLA provides a novel proof-of-concept for prostate cancer treatment.