19F MRI-Traceable PLGA Nanocarriers: Influence of Particle Architecture on Co-Encapsulation and Release of Immiscible Payloads

Two perfluorocarbon (PFC)-loaded PLGA nanoparticles (NPs) of different architectures were previously established as 19F MRI tracers: sodium cholate (NaCh)-stabilized core–shell particles (CSPs) and PVA-stabilized multicore particles (MCPs). Differing in their stabilizers and internal PFC distribution, they exhibited significant differences in stiffness, permeability, cell uptake, and biological behavior, with MCPs showing dramatically faster in vivo fluorine clearance, addressing an important barrier to the clinical translation of PFCs. Here, we explore the incorporation of rapamycin, a small hydrophobic drug, as a third immiscible phase to develop a theranostic platform for cardiac regeneration. By comparing the drug-loaded particle systems (Rapa-MCPs and Rapa-CSPs) against drug-free and PFC-free (Rapa-PLGA NPs) controls, we study how PFC presence and stabilizer-governed NP architectures affect multipayload incorporation, release, and biological behavior. PFC presence was associated with enhanced drug loading but faster release. A higher drug-to-polymer ratio increased loading but constrained PFC encapsulation above 2 wt %. NP architecture governed multipayload incorporation trade-offs: Rapa-CSPs showed preferential stabilization of the PFC phase over the drug and dye, and unpredictable drug release, reflecting greater sensitivity to multipayload incorporation; Rapa-MCPs could more flexibly accommodate multiple immiscible payloads at the expense of robust PFC stabilization, and showed a fast but gradual release. In vitro, encapsulated rapamycin retained mTOR-inhibitory activity, and Rapa-MCPs reduced TGF-β-driven fibrotic signaling in human living myocardial slices, supporting their therapeutic potential. These findings indicate that the stabilizers and resulting particle architectures govern payload partitioning and release in mutually immiscible multiphasic systems and provide practical design guidelines for structurally tunable polymer nanocarriers for 19F MRI-guided drug delivery.