Intrinsic Photoactive Star ZnPc–Poly(glutamate) Nanoplatforms for Multimodal Glioblastoma Therapy and Brain‐Targeted Delivery

ABSTRACT The design of polymeric systems with intrinsically integrated imaging and responsive functionalities represents a promising strategy to address the complexity of aggressive tumors such as glioblastoma multiforme (GBM). We report a class of star‐shaped zinc phthalocyanine–poly(L‐glutamic acid) (ZnPc‐PGA) nanocarriers in which the photoactive ZnPc core serves as a macroinitiator for the N‐carboxyanhydride ring‐opening polymerization, enabling control over chain length, architecture, and stoichiometry. ZnPc‐PGA nanocarriers exhibited near‐infrared absorption, enabling their implementation as imaging agents and photosensitizers for photodynamic therapy. Physicochemical characterization of ZnPc‐PGA nanocarriers revealed chain‐length‐ and concentration‐dependent supramolecular assembly. ZnPc‐PGA nanocarriers demonstrated lysosomal uptake/light‐activated cytotoxicity in GBM cells, while evaluation in the GBM‐on‐a‐chip platform confirmed oxygen‐dependent therapeutic outcomes. Proteomic profiling revealed a fibrinogen‐, cytoskeletal‐, and olfactory protein‐enriched corona, providing insight into potential biointerface interactions. Post‐polymerization conjugation of ZnPc‐PGA nanocarriers with paclitaxel facilitated multimodal therapy with enhanced efficacy in GBM cells, while integrating ZnPc‐PGA nanocarriers into a hyaluronic acid‐based hydrogel enabled intranasal delivery and resulted in brain accumulation. Overall, ZnPc‐PGA represents a modular nanoplatform and underscores the role of polymer architecture in dictating behavior in complex biological environments, with potential applicability in the design of multifunctional systems for challenging diseases such as GBM.