Co-delivering macrophage engager mRNA and PD-L1 antibody via tumor-responsive nanoparticles for glioblastoma immunotherapy.

Bispecific immune cell engagers, particularly bispecific T-cell engagers, show limited efficacy in solid tumors such as glioblastoma (GBM) due to systemic toxicities, poor T cell infiltration, and restricted drug penetration. We develop PL@mBiME, a multifunctional lipid nanoparticle (LNP) platform that enables brain tumor-targeted delivery and sustained in vivo expression of mRNA encoding a bispecific macrophage engager (BiME). The BiME simultaneously targets ErbB2 on glioma cells and CD206 on M2 macrophages, reprogramming macrophages toward pro-inflammatory M1 phenotype while promoting macrophage-tumor cell bridging, enhancing tumor cell phagocytosis and antigen presentation. PL@mBiME incorporates pH-responsive charge reversal to improve tumor accumulation and lysosomal escape as well as glutathione-triggered release of surface-conjugated PD-L1 antibody to amplify anti-tumor immunity. Across multiple GBM models, this coordinated activation of innate and adaptive immunity induces tumor regression, prolongs survival, and generates durable immune memory without significant toxicity.