Laser boosting the influx of calcium ions to enhance gasdermin e-dependent pyroptosis driven by a dual-layer polydopamine nanoagonist

As a recently revealed form of programmed cell death (PCD), pyroptosis can evoke a powerful inflammatory response and promote systemic immunity via a gasdermin E (GSDME)-dependent pathway. However, pyroptosis inevitably suffers from setbacks arising from the downregulated expression of GSDME and deficient caspase-3 activity in solid tumors. Herein, we designed a laser-boosted dual-layer polydopamine (PDA) hybrid nanoplatform (DMP@P) that codelivered decitabine (DCT) and mitoxantrone (MIT) to achieve high-efficiency pyroptosis. After reaching the tumor region, the PDA cloak is decomposed by the weakly acidic tumor environment, and the DCT released from the mesoporous polydopamine (MPDA) core upregulates GSDME expression by inhibiting DNA methylation. Moreover, near-infrared (NIR) laser irradiation causes a sharp influx of calcium ions (Ca2+), leading to cytochrome c release and cell dysfunction, which synergistically boosts caspase-3 activation by MIT. Activated caspase-3 cleaves upregulated GSDME by splitting the C-terminal region to generate the GSDME N-terminus (GSDME-N), and then GSDME-N aggregates to form pore-forming domains. Finally, inflammatory cytokines and antigens are rapidly released through the pores, which initiates extensive cell pyroptosis and induces an intense antitumor immune response to inhibit tumor proliferation and suppress metastasis. Overall, this nanoplatform with intrinsic biocompatibility provides inspiration for pyroptosis-induced cancer therapy.