Oncolytic Virus-like Nanoparticle Targets the Golgi Apparatus via Sphingomyelin

Abstract

Abstract The Golgi apparatus (GA) has emerged as a promising target for cancer therapy. Commonly, therapeutics are guided to the GA by recognizing specific receptors on the GA membrane. However, the low and heterogeneous expression of these receptors often results in suboptimal targeting efficiency. Here, we present an oncolytic virus-like nanoparticle for GA targeting by exploiting sphingomyelin, an abundant component of the GA membrane. This nanoparticle consisted of a polymeric nanocarrier complexed with a plasmid encoding the secreting peptide-deleted α-hemolysin (αHL), a pore-forming protein with high affinity for sphingomyelin. The nanoparticle could transfect cancer cells to induce intracellular expression of αHL, enabling GA targeting through binding to GA-associated sphingomyelin while bypassing the cell membrane. Consequently, the transfected cells exhibited GA structural disassembly and underwent a pyroptosis-like programmed cell death with immunogenic characteristics. Notably, αHL-rich microvesicles were subsequently secreted, effectively killing neighboring tumor cells. Intratumoral administration of this formulation significantly suppressed subcutaneous tumor growth and elicited robust antitumor immunity, preventing tumor rechallenge. Furthermore, by incorporating iRGD-modified polymers, we constructed a tumor-targeting oncolytic virus-like nanoparticle with neutral surface charge. Following intravenous administration, this iRGD-modified nanoparticle could efficiently suppress tumor growth without causing obvious systemic toxicity. Collectively, this work presents a robust strategy for GA-targeting via sphingomyelin recognition, providing a potential approach for GA-targeted anticancer therapeutics.