纳米颗粒溶解微针（DMN）由于其能够提供高载药量、可调节的药物释放行为和提高的治疗效率而引起了越来越多的关注。然而，由于促进纳米粒子渗透的驱动力不足以及缺乏指导制剂设计的体内命运研究，此类递送系统仍然面临着药物递送效率不理想的问题。在此，聚集引起的猝灭（ACQ）探针（P4）被封装在基于l-精氨酸（l-Arg）的纳米胶束中，其进一步配制为一氧化氮（NO）驱动的纳米胶束集成DMN（P4/l- Arg NMs@DMNs）来研究它们的生物学命运。 P4探针可以在完整的纳米胶束中发出强烈的荧光信号，同时随着纳米胶束的解离而猝灭，为跟踪纳米胶束在不同状态下的命运提供了一种“可区分”的方法。 l-Arg 被证明可以在活性氧 (ROS) 过多的肿瘤微环境下自生成 NO，提供气动力以促进纳米胶束在三维 (3D) 培养的肿瘤细胞和黑色素瘤小鼠中的渗透。与没有NO推进剂的被动微针（P4 NMs@DMNs）相比，P4/l-Arg NMs@DMNs具有良好的NO生产性能和更高的纳米粒子穿透能力。总之，本研究提供了一种基于 ACQ 探针的生物命运追踪方法，以证明 NO 驱动的纳米颗粒负载 DMN 在增强局部肿瘤治疗渗透方面的潜力。

Nanoparticle-loaded dissolving microneedles (DMNs) have attracted increasing attention due to their ability to provide high drug loading, adjustable drug release behavior, and enhanced therapeutic efficiency. However, such delivery systems still face unsatisfied drug delivery efficiency due to insufficient driving force to promote nanoparticle penetration and the lack of in vivo fate studies to guide formulation design. Herein, an aggregation-caused quenching (ACQ) probe (P4) was encapsulated in l-arginine (l-Arg)-based nanomicelles, which was further formulated into nitric oxide (NO)-propelled nanomicelle-integrated DMNs (P4/l-Arg NMs@DMNs) to investigate their biological fate. The P4 probe could emit intense fluorescence signals in intact nanomicelles, while quenching with the dissociation of nanomicelles, providing a "distinguishable" method for tracking the fate of nanomicelles at a different status. l-Arg was demonstrated to self-generate NO under the tumor microenvironment with excessive reactive oxygen species (ROS), providing a pneumatic force to promote the penetration of nanomicelles in both three-dimensional (3D)-cultured tumor cells and melanoma-bearing mice. Compared with passive microneedles (P4 NMs@DMNs) without a NO propellant, the P4/l-Arg NMs@DMNs possessed a good NO production performance and higher nanoparticle penetration capacity. In conclusion, this study offered an ACQ probe-based biological fate tracking approach to demonstrate the potential of NO-propelled nanoparticle-loaded DMNs in penetration enhancement for topical tumor therapy.