A cost-performance index for nano-optical biosensor evaluation: Systematic evaluation of europium-salicylate luminescent platforms for GPC3-targeted early HCC diagnosis.

Comparative evaluation of nano-optical biosensor platforms lacks a standardised, multi-parameter quantitative framework that integrates analytical performance with practical deployability - a critical gap for translating laboratory-validated sensors into resource-constrained clinical settings. This critical review addresses that gap by proposing a ten-parameter Cost-Performance Index (CPI) and applying it to europium-salicylate (Eu-SA) luminescent complexes in sol-gel and polymeric matrices as a novel, cost-accessible biosensor class for time-resolved optical detection of glypican-3 (GPC3), an early-stage hepatocellular carcinoma (HCC) serum biomarker. Four analytical chemistry contributions are made: (i) the CPI framework itself - to the best of our knowledge, the first reproducible, literature-derived instrument scoring seven biosensor platforms across ten parameters (LOD, selectivity, cost efficiency, POC readiness, stability, clinical translation readiness, multiplexing, sample preparation, fabrication scalability, and regulatory maturity) under both laboratory-weighted and POC-weighted schemes, with all raw scores reported to enable independent recalculation; (ii) the first systematic mechanistic characterisation of salicylic acid as a low-cost antenna ligand (<$0.05/g) conferring long luminescence lifetimes (>1 ms) and narrow 615 nm emission via efficient ligand-to-metal energy transfer; (iii) a transparent synthesis of published molecular docking, MD, and Finite-Difference Time-Domain (FDTD) simulation results as computa-tional design predictions, explicitly distinguished from experimentally confirmed outcomes; and (iv) a structured characterisation of the translational evidence gaps that must be closed before Eu-SA GPC3 biosensors can enter clinical deployment. Cross-domain validation of the CPI framework is demonstrated by applying identical scoring to five cardiac troponin I (cTnI) nano-biosensor platforms: the resulting POC-weighted rankings are structurally consistent with the GPC3 domain, confirming the framework's generalisability across clinically distinct analytes and platform lit-eratures. The current evidence base for Eu-SA GPC3 biosensors consists of analytical validation in spiked human serum and rodent models only. No prospective multi-centre clinical cohort data are available. This limitation is discussed explicitly throughout. The review concludes that Eu-SA platforms represent a promising, cost-accessible sensing strategy warranting rigorous clinical validation - not a demonstrated superiority at this stage of evi-dence. Disclosure: The primary analytical performance data for Eu-SA GPC3 biosensors reported herein derive from two prior publications originating from the laboratories of Ain Shams University (Cairo, Egypt) and Imam Mohammad Ibn Saud Islamic University (Riyadh, Saudi Arabia), institutions represented in this authorship. In-dependent replication of these data by external laboratories has not yet been reported in the peer-reviewed literature. Accordingly, the Cost-Performance Index ranking assigned to the Eu-SA platform is presented as an illustrative application of the proposed framework and should not be interpreted as a definitive determination of platform superiority.