Self‐Delivering Nanodrugs Developed via Small‐Molecule‐Directed Assembly and Macrophage Cloaking for Sonodynamic‐Augmented Immunotherapy

The self-delivery of sonosensitizers and immunomodulators to tumor areas, which is highly recommended for enhancing sonodynamic immunotherapy, remains a challenge. Herein, a self-delivering nanodrug (HB-NLG8189, drug loading: ≈100 wt%) is developed by the small-molecule self-assembly of "HB" (a new clinical photosensitizer) and NLG8189 (indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor) for sonodynamic-augmented immunotherapy; this preparation method ensures the absence of excipient-related toxicity and immunogenicity. To evade immune recognition and prolong the circulation time, the HB-NLG8189 nanodrugs are camouflaged using macrophage cell membranes (MPCMs). The constructed HB-NLG8189@MPCM nanodrugs show an ability to preferentially accumulate within tumors. Upon ultrasound triggering, the HB-NLG8189@MPCM is able to generate reactive oxygen species efficiently for robust sonodynamic therapy; it induces immunogenic cell death, initiates an antitumor immune response to activate tumor-specific effector T cells, and promotes the secretion of inflammatory cytokines. The concomitant delivery of NLG8189 reverses the immunosuppressive tumor microenvironment by restraining IDO-1 activation and the intratumoral infiltration of regulatory T cells. Sonodynamic-augmented immunotherapy with HB-NLG8189@MPCM significantly inhibits the growth of both primary and distant tumors with little systemic toxicity. The biomimetic self-delivery nanodrug provides a promising paradigm for improving sonodynamic immunotherapy.