Self-reinforcing nanomedicine orchestrates EPR effect and neutrophil hitchhiking for spatiotemporal accumulation in solid tumors.

Targeted drug delivery remains pivotal for enhancing therapeutic efficacy in cancer treatment. While nanomedicines harness the enhanced permeability and retention (EPR) effect for passive tumor accumulation, their efficacy is often hindered by physiological barriers that limit optimal delivery. Active delivery strategies by immune cell (neutrophils etc.) hitchhiking offer a promising approach to surmount these obstacles; however, attenuated tumor-associated inflammation restricts their tumor-directed migration. Here, we present a biomimetic nanoplatform based on polydopamine nanoparticles coated with bacterial outer membrane vesicles (OMV@PDA). Upon single injection, these nanoparticles not only passively accumulate in tumors via the EPR effect and generate localized hyperthermia under near-infrared irradiation to ablate tumor cells and trigger inflammation, but also leverage their pathogen-mimicking coating to promote efficient uptake by circulating neutrophils (83.2% phagocytosis rate). The photothermally amplified inflammation broadcasts "find-me" signals to recruit nanoparticle-laden neutrophils to tumor sites. Consequently, a single injection orchestrates EPR effect and neutrophil hitchhiking for spatiotemporal accumulation, achieving high-intensity and sustained tumor accumulation. Notably, this strategy yielded an remarkable tumor inhibition rate of 95%, underscoring superior therapeutic efficacy. Our findings establish a self-reinforcing paradigm for advancing targeted drug delivery in oncology.