Synergistic HER2-scFv mediated immunotherapy with targeted gemcitabine delivery harnessing biomimetic composite nanoparticles for enhanced metastatic tumor therapy

Metastatic breast cancer poses a formidable challenge to global female health and public hygiene. Patients with HER2⁺ breast cancer typically demonstrate higher mortality rates and rapid recurrences. Despite the notable advantages in high effectiveness and precision for HER2⁺ cancer therapy, ADCs (Antibody-Drug Conjugates) still face limitations in rapid metabolism and off-target toxicity <i>in</i> <i>vivo</i>. Recently, biomimetic cell membranes camouflaged nanocarriers exhibits remarkable capabilities in immune escape, extended drug circulation in the bloodstream, and enhanced targeted accumulation at tumor sites. In response, PLGA nanoparticles with engineered modified macrophage membrane coating was designed to develop a novel gene reprogramming biomimetic drug-loading nanoplatform. The nanoplatform enabled anti-HER2 antibodies to be stably expressed on the macrophage membrane (HM), making it more effective against HER2⁺ tumor cells, achieving precise targeted delivery of near-infrared (NIR) fluorescent dye IR780 or chemotherapy drugs GEM. When compared to nanoparticles coated with traditional macrophage membranes, GEM@PLGA@HM demonstrated outstanding HER2-targeting proficiency both <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i>. Imaging studies conducted on small animals further verified the precise accumulation of GEM@PLGA@HM specifically within HER2⁺ tumors. When combined with HER2 antibodies, GEM treatment exhibited a marked improvement in antitumor effects, both <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i>. Notably, the combined therapy demonstrated a significant 14-fold increase in cytotoxicity against HER2⁺ metastatic cancer cells (SK-OV-3) in comparison to GEM used alone, which was further proved mechanistically that GEM@PLGA@HM operated synergistically to hinder the progression and metastasis of HER2⁺ tumors by triggering apoptosis and concurrently inhibiting the PI3K/AKT and MAPK signaling cascades. This biomimetic nanoplatform represents a powerful tool for targeted chemotherapeutic delivery and holds great promise for the treatment of HER2⁺ primary and metastatic breast cancer.