– Fig. 1A/C vs. text: pHLIP insertion is shown at pH 6.5, yet the hydrogel shell is assembled under “mild physiological conditions” (pH 7.4). How is HRP displayed for HA-DA crosslinking at pH 7.4? What evidence supports “reversible” pHLIP anchoring without membrane perturbation?
– Fig. 1C: Far-red light only stops transcription; it cannot halt secretion of already translated IFN-γ, IL-6, or anti-CD47 antibody. Also, releasing IL-6 and IFN-γ in a therapy intended to avoid cytokine release syndrome is a direct safety contradiction. What are the local/systemic exposure and CRS safeguards?
– Fig. 1B: How does the hydrogel block macrophages/DCs while allowing ~150 kDa antibodies and cytokines to diffuse out? What is the molecular weight cutoff? If HA is crosslinked into the shell, how does it still achieve tumor-specific CD44 targeting given ubiquitous CD44 and normal HA? Encapsulated HEK293T cells exceed pulmonary capillary diameter—how do they avoid embolization?
– Clinical translation: Fiber-optic bronchoscopy/thoracoscopy is invasive and cannot access all deep intrapulmonary micrometastases, contradicting the stated goal of “noninvasive optical control.” How will multiple lesions be illuminated?
– Terminology/typos: “bistable” vs. reversible red/far-red switch; “ΔPhyA” vs. “FH1-1α-PhyA”; “interferon-γ anti-CD47 antibodies, andinterleukin-6” needs clarification.
