Smart Tumor Cell‐Derived DNA Nano‐Tree Assembly for On‐Demand Macrophages Reprogramming

Abstract Without coordinated strategies to balance the population and activity of tumor cells and polarized macrophages, antitumor immunotherapy generally offers limited clinical benefits. Inspired by the “eat me” signal, a smart tumor cell‐derived proximity anchored non‐linear hybridization chain reaction (Panel‐HCR) strategy is established for on‐demand regulation of tumor‐associated macrophages (TAMs). The Panel‐HCR is composed of a recognition‐then‐assembly module and a release‐then‐regulation module. Upon recognizing tumor cells, a DNA nano‐tree is assembled on the tumor cell surface and byproduct strands loaded with CpG oligodeoxynucleotides (CpG‐ODNs) are released depending on the tumor cell concentration. The on‐demand release of CpG‐ODNs can achieve efficient regulation of M2 TAMs into the M1 phenotype. Throughout the recognition‐then‐assembly process, tumor cell‐targeted bioimaging is implemented in single cells, fixed tissues, and living mice. Afterward, the on‐demand release of CpG‐ODNs regulate the transformation of M2 TAMs into the M1 phenotype by stimulating toll‐like receptor 9 to activate the NF‐κB pathway and increasing inflammatory cytokines. This release‐then‐regulation process is verified to induce strong antitumor immune responses both in vitro and in vivo. Altogether, this proposed strategy holds tremendous promise for on‐demand antitumor immunotherapy.