Dual-engineered, "Trojanized" macrophages bio-modally eradicate tumors through biologically and photothermally deconstructing cancer cells in an on-demand, NIR-commanded, self-explosive manner.

Abstract

To engineer tumor-tropic cells as drug delivery vehicles is a promising strategy to improve therapeutic specificity and efficacy for cancer treatment. However, conventional genetically engineered cell-based drug delivery systems are often capable of initiating single-mode therapy, and lack precise spatiotemporal control over the release of therapeutic payloads at tumor local, thus possibly causing severe systemic toxicity. Here, the macrophages are genetically engineered to encode a non-secreted form of EGFP-TNFα fusion protein and intracellularly carry near-infrared (NIR)-responsive heat-nanogenerators (HIMs). Owing to macrophages' intrinsic tumor tropism and HIMs' photo-responsiveness to NIR, these macrophages (HIMs@eM^ET) can actively accumulate at tumor sites and undergo controlled photothermolysis induced by NIR-induced HIMs-mediated photothermal effects (PTE). Such heat-induced cell explosion enables spatiotemporally controlled release of non-secreted TNFα from macrophages and effectively kills cancer cells. Importantly, in a preclinical tumor model, HIMs@eM^ET actively migrate to tumors where PTE and released EGFP-TNFα exhibit an enhanced antitumor effect, suppressing tumor growth and significantly prolonging animal survival without eliciting adverse side effects. Thus, this study demonstrates the potential of such dual-engineered macrophages in bi-modal cancer therapy.