Nanoparticle-based T-cell engagers: from T-cell redirection to programmable immune platforms

Bispecific T-cell engagers (BTCEs) have emerged as a powerful class of cancer immunotherapies that redirect endogenous T cells toward malignant cells through the simultaneous binding of T cells and cancer cells via tumor-associated antigens (TAAs). Despite remarkable clinical success, particularly in hematologic malignancies, conventional BTCEs face significant limitations, including short circulation half-lives, rapid renal clearance, antigen-loss-mediated resistance, and reduced efficacy in solid tumors due to the immunosuppressive tumor microenvironment (TME). Nanoparticle-based bispecific T-cell engagers (nanoBTCEs) have been developed to address these challenges by combining the immune-engaging capabilities of BTCEs with the pharmacokinetic and engineering advantages of nanomedicine. In this review, we discuss how nanotechnology expands the therapeutic capabilities of T-cell engagers beyond simple immune redirection. NanoBTCEs enhance T-cell recruitment and tumor engagement through multivalent interactions, improve pharmacokinetic properties, and enable multifunctional therapeutic strategies through the incorporation of immunomodulatory payloads, therapeutic cargos, and imaging agents. Emerging platforms have demonstrated the ability to modulate the TME, reverse T-cell dysfunction and exhaustion, integrate theranostic functionalities, and overcome tumor heterogeneity and antigen escape through multispecific targeting approaches. Altogether, these advances position nanoBTCEs as versatile immunotherapeutic platforms rather than simple T-cell-engaging agents. We further discuss key translational challenges, outstanding biological questions, and future design principles for next generation nanoBTCEs. As the fields of nanotechnology and immunoengineering continue to converge, nanoBTCEs are evolving into programmable immune platforms capable of integrating T-cell redirection, precision delivery, TME modulation, and multimodal therapeutic functions within a single construct. Collectively, these advances highlight the potential of nanoBTCEs to overcome several limitations of conventional BTCEs and broaden the clinical utility of T-cell-based cancer immunotherapies.