Finely tunable NIR-II organic scaffolds for fluorescence/photoacoustic duplex imaging–guided noninvasive photothermal therapy of glioblastoma

Organic agents possessing NIR-II and photoacoustic duplex imaging capabilities, coupled with high-efficiency photothermal conversion, offer significant potential for noninvasive and precise phototheranostics of glioblastoma, which is further augmented when these agents can concurrently exhibit tumor targeting and blood–brain barrier (BBB) permeability. This study reports a series of finely tunable NIR-II molecular luminophores based on the aza-BODIPY scaffold, featuring unique twisted and rotatable structures. They are further constructed to folate-decorated polymeric nanoparticles, exhibiting remarkable NIR-II/photoacoustic imaging performance and superior photothermal conversion efficiency (49.7%). Folate modification enables tumor targeting and BBB permeability through receptor-mediated transcytosis, allowing for precise and efficient phototherapy in 4T1-/glioblastoma-bearing mice after a single intravenous injection and irradiation. This study presents a rational molecular engineering approach and a versatile structural scaffold for designing NIR-II emitters with tailored photophysical properties and desirable phototherapeutic efficacy, thereby offering novel perspectives on the development of advanced depth imaging probes and brain tumor therapeutics.