NIR-II AIEgen with high photothermal efficiency for mild PTT: Optimized natural killer cell spatial distribution for boosted immune response.

Organic photothermal agents (PTAs) with high photothermal conversion efficiency (PCE) and biocompatibility are ideal for mild photothermal therapy (PTT), which can selectively eliminate tumor cells and elicit an active immune response. However, the challenge lies in developing PTAs with high PCE, and the impact of PTT-induced temperature gradients on the cytolytic potential of natural killer (NK) cells against tumor cells has yet been investigated. Herein a novel NIR-II aggregation-induced emission (AIE) molecule named C12T-BBT is proposed by conjugating an electron donor TPA with a strong electron acceptor BBT, using a long alkyl chain (C12) substituted thiophene as π-bridge. By doing this, C12T-BBT has a relative planar structure to ensure a high extinction coefficient, while the long alkyl chain restricts the π-π interaction and provides more room for molecular motion in excited state. Together, these design strategies assure C12T-BBT with a high PCE of 84.7 %. In vivo experiments exhibit favorable NIR-II imaging and tumor elimination using water-soluble cRGD@C12T-BBT nanoparticles. The application of mild PTT results in an effective induction of NK cell response in terms of shortening its distance with tumor cells from 25.6 μm to 10.6 μm, characterized using a machine-learning based spatial analysis, thereby enhancing the efficacy of cancer therapy. Therefore, this work provides evidence for a novel combined anti-tumor strategy of aligning mild PTT and NK cell immunotherapy by illustrating crucial optimization of NK-tumor intercellular proximity in mild PTT.