Abstract 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.
Zhang et al. (Sat,) studied this question.