Abstract

Site-specific drug delivery and minimizing the off-target actions of pharmaceuticals are among the primary pursuits in drug development research with a special emphasis on anticancer drugs targeting metastatic tumors. Here, we show that large-sized and stiff lipid nanoparticles (LNP-L), fabricated via a modified microfluidic process and composed of clinically approved excipients, exhibit the capability of abdominal cavity retention via intraperitoneal (IP) administration. In addition, the clodronate-loaded lipid nanoparticles (Clodro-LNP-L) enable localized depletion of peritoneal macrophages while sparing blood monocytes and macrophages in other tissues. The peritoneal-specific removal of macrophages by Clodro-LNP-L preserves the systemic antimicrobial capability, whereas the commercial clodronate liposomes significantly increase the infection risk of S. aureus-induced pneumonia and sepsis in murine models. Importantly, Clodro-LNP-L effectively inhibits tumor implantation and metastasis in two murine models of peritoneal metastasis (PM) of colon and gastric cancer, respectively. Meanwhile, the macrophage depletion induced by Clodro-LNP-L synergizes with the first-line chemotherapy drug oxaliplatin (OXP) to prolong the overall survival of mice bearing colorectal PM. Our findings suggest a potential clinically translatable strategy for treating PM via localized depletion of macrophages.