Interfacial structural-functional modulation of PLA-TPGS macromolecular assemblies for synergistic Tri-modal...

The performance of a multifunctional nanotheranostic depends on how its macromolecular assembly controls the loaded agents at the interface. Here, we report a bio-based nanoplatform (M8) built from an amphiphilic poly(lactide)-TPGS matrix and designed for colorectal cancer theranostics. Beyond efficient co-encapsulation (>85%), the controlled assembly of these segments gives a stepwise structural amplification of transverse relaxivity (r₂), reaching 255.04 mM^-1⋅s^-1 (r₂/r₁ = 455.84). This 3.4-fold gain at 7 T, higher than common clinical iron-oxide agents, comes from local magnetic field inhomogeneities and slower water-proton diffusion. Molecular crowding and homo-FRET first lower the NIR emission inside the core, but this turns into a fluorescence dequenching effect that reveals tumour accumulation in CT26 colorectal cancer models. The lipophilic PPIX, owing to its lipophilicity, is expected to localize preferentially toward the polymer shell, supporting interfacial ROS generation; together with magnetic hyperthermia and doxorubicin chemotherapy, the platform delivers a triggered multimodal cytotoxic response. Under combined laser and alternating magnetic field, the cytotoxicity increased 13-fold for M8 (IC₅₀ from 12.31 to 0.95 µg/mL) and 29-fold for M4 (from 3.51 to 0.12 µg/mL), while normal Vero cells stayed largely unaffected (IC₅₀ 23-30 µg/mL), giving an in vitro therapeutic window above 30-fold. In CT26 tumour-bearing mice, M8 gave strong T2 signal darkening in the tumour, with 4.4- and 6-fold rises in the low- and high-signal pixel fractions, and NIR imaging confirmed tumour retention beyond 24 h. These results show how the colloidal structure links imaging and therapeutic performance, and offer a practical design route for colorectal cancer theranostics.