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X-ray reflectivity-guided design of porphysomes for improved photodynamic cancer therapy

• Porphysomes, lipid-based nanostructures loaded with porphyrins, show significant potential for light-based cancer treatment but require structural optimisation to improve delivery and therapeutic effect. • X-ray reflectivity measurements at beamline ID10 provided detailed information on the thickness and organisation of the porphysome membranes, guiding adjustments to improve how the porphyrin molecules are arranged. • These structural insights indicated that more ordered membranes enhance the light-activated response, supporting the development of more effective porphysome-based cancer therapies.

Fig. 1: a) Chemical structures of a representative PL-Por conjugate and cholesterol used for porphysome formulation. b) The porphysome bilayers were modelled as monolayers compressed to a surface pressure of 30 mN/m at the air–water interface, where

their structure normal to the interface was probed using XRR. c) XRR curves were fitted using a two-slab model, and (d) electron density profiles were reconstructed. The results demonstrate a clear thickening of the monolayer accompanied by reduced roughness.

The challenge

Porphysomes [1,2] are light-responsive, liposome-like nanoparticles formed from supramolecular assemblies of phospholipid–porphyrin (PL-Por) conjugates [3]. In their intact form, they exhibit strong photothermal activity but limited photodynamic efficacy due to low reactive oxygen species generation, which constrains their usefulness for photodynamic therapy (PDT).

To address this limitation, recent efforts have focused on designing porphysomes that undergo controlled photo-induced disruption, releasing active porphyrins to enhance photodynamic performance. This work aimed to develop a new class of light-responsive porphysomes capable of porphyrin release upon photoactivation.

The experiment

To formulate stable and responsive porphysomes, the structural organisation of PL-Por conjugates in monolayers at the air–water interface was investigated using X-ray reflectivity (XRR) at beamline ID10-SURF.

The chemical structures of representative PL-Por conjugates and cholesterol are shown in Figure 1a. XRR measurements were performed on monolayers compressed to a defined surface pressure (Figure 1b), allowing the fine structure of the assemblies normal