Single‐Cell RNA‐Sequencing‐Aided Covalent Organic Frameworks‐Based Microneedle Design Targeting Phototherapy Resistant Tumor Cell

Abstract Covalent organic frameworks (COFs) exhibit immense potential for phototherapy due to their exceptional light absorption, photostability, and biocompatibility. Nevertheless, tumor cells can develop resistance to phototherapy after an initial response, posing a significant challenge for complete eradication. In this study, a COF‐based photosensitizer, TCN‐PPDA‐COF, is designed with outstanding photothermal properties and delivered to tumors using microneedles (MN) to enhance cancer phototherapy. Single‐cell RNA‐sequencing (scRNA‐seq) technology is then utilized to explore the mechanisms underlying tumor cell adaptation to COF‐mediated phototherapy. The scRNA‐seq analysis revealed that phototherapy‐resistant tumor cells displayed elevated expression of HIF‐1α and VEGF signaling pathways, fostering intratumoral angiogenesis and facilitating their continued survival during phototherapy. In response to this phenomenon, a unique CA‐microneedle (MN) patch is developed, tailored for co‐delivering TCN‐PPDA‐COF and angiogenesis inhibitors AL3818 to the tumor site. The CA‐MN patches can effectively inhibit angiogenesis in tumors while mediating phototherapy, thereby obliterating the phototherapy‐resistant tumor cells. In 4T1 tumor‐bearing mouse model, the CA‐MN patches achieved nearly complete regression of tumor grafts and activated host anti‐tumor immunity, thereby enhancing the response rate of αPD‐1 and effectively restraining tumor metastasis and recurrence. This study underscored an ingenious approach to modify COF‐MN patches through scRNA‐seq technology.