Cascade-Targeting Apoptosis via Synergy of TRAIL-Specific Bystander Effect and Mitochondrial Photodamage in Cancer Therapy

Tumor-specific apoptosis exerts considerable curative efficacy in cancer, particularly with TRAIL, which has been approved in the clinic; however, therapeutic outcome is compromised due to apoptosis evasion and the short half-life of exogenously infused TRAIL. Herein, we propose a synergistic apoptosis strategy of orthotopic TRAIL expression for enhancing the bystander effect and mitochondrial photodamage for intrinsic apoptosis activation. To actualize synergetic apoptosis, we develop cascade-targeting nanoparticles to perform cell-to-mitochondria shuttling, in which TRAIL-expressing plasmid (pTRAIL) is coprecipitated with calcium phosphate on a glycyrrhetinic acid (GA)-modified graphene oxide nanosheet. For apoptosis synergy, GA mediates tumor accumulation of nanoparticles, followed by structure dissociation for efficient pTRAIL release and expression (cascade module I). Thereafter, GA-modified graphene carriers perform mitochondria distribution for laser-triggered photodamage (cascade module II). The nanoparticles yield tumor inhibition of 86.78% in the melanoma model and demonstrate metastasis blocking activity. Collectively, a cascade-targeting apoptosis technology via a combination of TRAIL-specific bystander effects and mitochondrial photodamage provides innovative oncotherapy synergy.