Next-generation therapeutic triggers for on-demand, site-specific, enzyme-gated prodrug and nanocarrier systems

초록

The advent of precision oncology and targeted therapeutics has transformed cancer treatment. Activation of cytotoxic and therapeutic agents in patients remains largely non-specific, driven by systemic metabolism rather than tumor-specific cues. A unique opportunity for precision-gated drug activation exists in esterase-responsive DDS, where esterase expression, isoform distribution, and subcellular localization vary greatly between tissues, tumor types, and patients. Despite the widespread use of ester linkers in prodrugs and nanomedicines, most prior studies and reviews have treated esterification as a generic strategy for improving pharmacokinetics, without systematically addressing where, by which esterases, and under what microenvironmental conditions drug activation occurs in vivo. In this review, we reposition esterase biology as a central design constraint and enabling biomarker for precision drug activation. Integrating recent primary literature (2022-2025) with mechanistic insights into human carboxylesterase (CES) isoforms, we derive explicit linker design rules that connect ester chemistry, steric accessibility, and positioning to CES1/CES2 selectivity and tissue-biased activation. We further discuss how nanocarrier architectures can amplify esterase responsiveness, coupling enzymatic cleavage to carrier disassembly, membrane destabilization, and controlled intracellular release, with direct consequences for pharmacokinetics, tumor selectivity, and systemic toxicity. Beyond single-trigger systems, we analyze emerging dual and multi-stimuli platforms combining esterase responsiveness with hypoxia, redox, or reactive oxygen species cues as logic-gated precision therapies capable of overcoming intratumoral heterogeneity and off-tumor activation. Finally, we discuss the translational implications and biosafety considerations, highlighting how esterase-gated strategies can align with patient stratification, imaging-guided activation, and clinically validated platforms such as liposomal irinotecan. Using a systematic approach that incorporates esterase isoform biology, linker chemistry, nanocarrier design, and microenvironment-programmable logic, this review outlines a framework for developing patient-tailored, esterase-responsive therapeutics for precision oncology in the future.

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