Lysosome-Bursting Calcium Carbonate Nanoparticles Amplify Immunogenic Cell Death via Synergistic Phototherapy and Calcium Overload for Immune Checkpoint Blockade

Abstract

Immunogenic cell death (ICD) induction is a promising strategy to enhance cancer immunotherapy, yet its efficacy is often limited by insufficient immune activation. Herein, we develop a lysosome-bursting calcium carbonate nanoplatform (cRGD/MD@ICN) co-loaded with the photosensitizer indocyanine green (ICG) and a PD-L1 inhibitory peptide (DPPA-1) for synergistic phototherapy and calcium overload to amplify ICD and potentiate immune checkpoint blockade. The nanoparticle is decorated with cRGD for active tumor targeting and a matrix metalloproteinase-2 (MMP-2)-cleavable linker (MD) for on-demand release of DPPA-1 in the tumor microenvironment. Upon endocytosis into tumor cells, the acidic lysosomal environment triggers rapid dissolution of the calcium carbonate core, releasing ICG and Ca2+, leading to lysosome bursting and subsequent calcium overload. Combined with near-infrared (NIR) irradiation, ICG-mediated phototherapy and calcium overload synergistically induce robust ICD, characterized by enhanced calreticulin exposure, HMGB1 release, and ATP secretion. In vivo studies demonstrate that cRGD/MD@ICN significantly suppresses orthotopic breast tumor growth and pulmonary metastasis by promoting dendritic cell maturation and intratumoral infiltration of CD4+ and CD8+ T cells. This lysosome-bursting nanoplatform offers a promising strategy to amplify ICD through synergistic phototherapy and calcium overload, thereby boosting the efficacy of immune checkpoint blockade for cancer treatment.