Ion-pair-engineered nanoassemblies for synergistic integration of type I and II immunogenic cell death and chemo-photo-immunotherapy

Immunotherapy currently benefits only a small fraction of patients due to low tumor immunogenicity. Immunogenic cell death (ICD) is an effective strategy to stimulate tumor immunogenicity by integrating antigenicity and adjuvanticity. Type I and type II ICD inducers trigger cell death and immune adjuvant release through distinct pathways. Current strategies typically focus on a single type-inducer strategy, which shows limited efficacy. To overcome this limitation, we developed ion-pair-engineered nanoassemblies (hypericin-mitoxantrone nanoassemblies [H-M NAs]) to co-encapsulate a type I ICD inducer (chemotherapeutic mitoxantrone [MTO]) and a type II ICD inducer (photosensitizer hypericin [HY]). The NAs integrate chemotherapy and phototherapy to generate tumor antigens and enhance immune adjuvant exposure via distinct pathways. As a result, H-M NAs significantly amplify the ICD effect and improve the antitumor response. This work provides insight into the synergy of type I and type II ICD inducers for enhancing tumor immunogenicity in cancer treatment.