Next-Generation Molecular Diagnostics for Sepsis: Toward a SPICE-Based Diagnostic Architecture

Sepsis remains a major cause of mortality and healthcare burden worldwide, and delays in identifying infectious etiologies and clinically actionable diagnostic signals continue to compromise the timely initiation of appropriate antimicrobial therapy and patient outcomes. Conventional blood culture methods are limited by prolonged turnaround times, while recent advances in molecular diagnostic technologies have significantly improved the speed and sensitivity of pathogen detection. These advances highlight the potential of rapid and accurate molecular diagnostics to support timely diagnosis and targeted treatment. However, as analytical performance continues to improve, the major bottlenecks have increasingly extended beyond individual assay performance to workflow integration, operational complexity, and clinical implementation. Current platforms still face inherent trade-offs among diagnostic performance, cost, automation, and usability, limiting their widespread clinical adoption. To address these challenges, we propose the SPICE framework, encompassing Speed, Precision, Intelligence, Cost, and Ease of Use, as a unified perspective for evaluating existing technologies and guiding the design of next-generation molecular diagnostic systems. Based on these five interconnected dimensions, this review synthesizes recent advances in nucleic acid amplification, sequencing, multiplex detection, data-driven analysis, and sample-to-answer diagnostic platforms within a unified system-level framework, and compares representative approaches according to their SPICE-based capability profiles, major strengths, and limitations. These analyses further identify key barriers to clinical translation and the system-level requirements for the development and clinical implementation of intelligent, integrated sample-to-answer molecular diagnostic platforms for sepsis.