Intracellular Delivery of Mitochondria-Targeting Cationic Polypeptides by pH-Responsive Nanoparticles to Induce Immunogenic Cell Death

Targeted induction of mitochondrial dysfunction by cationic polypeptides represents a promising strategy for inducing immunogenic cell death (ICD). Nevertheless, cationic polypeptides face challenges in systemic application due to poor tumor selectivity and inherent toxicity caused by their positive charges. Herein, a pH-responsive nanoparticle (CA-NP) is prepared through electrostatic self-assembly of a mitochondria-targeting cationic polypeptide (MTP) and an acid-sensitive anionic polypeptide. CA-NPs effectively shield the positive charges and improve the intratumoral accumulation of MTP. Upon cellular uptake, the pH-responsive CA-NPs can dissociate within acidic endolysosomes to release MTP. Following endolysosomal escape, the liberated MTP selectively localizes to mitochondria, causing mitochondrial damage and stimulating intracellular reactive oxygen species generation, which ultimately induces ICD. Consequently, CA-NPs substantially enhance the biosafety profile of MTP while effectively suppressing tumor growth through mitochondrial disruption and systemic antitumor immune activation. Together, these findings position pH-responsive CA-NPs as a promising therapeutic platform that could improve both the precision and the safety of cationic polypeptide-based cancer immunotherapy.