Combined Polyamine Key Nanoformulations as Anticancer Therapeutics: Review of the Evidence

Abstract: Polyamine metabolism offers several entry points for cancer nanotherapy, but pathway inhibition, carrier uptake and catalytic cytotoxicity require different evidence. This review examines how nanosystems address compensatory polyamine uptake, normal-tissue exposure and mismatched delivery of combination treatments. We organize the literature by four non-exclusive mechanisms: Deplete reduces a required polyamine pool; Disrupt alters feedback or releases active analogs; Exploit uses experimentally demonstrated transport-associated uptake; and Convert transforms polyamines into reactive products. Representative systems include self-immolative analog carriers, polyamine-decorated particles and enzyme-containing frameworks or local hydrogels. Their reported advantages remain dependent on formulation, administration route and tumor model. We connect material properties to target engagement, adaptive glutamine and arginine metabolism, immune effects and the controls needed to establish a causal nano-enabled benefit. Clinical efficacy of conventional eflornithine in a defined neuroblastoma setting provides pathway validation, whereas the polyamine-directed nanosystems reviewed here remain preclinical. Translation requires exposure-matched comparisons, quantitative tumor-to-normal-tissue pharmacology, repeat-dose recovery and reproducible manufacturing. The framework is intended to guide experimental design and critical comparison, rather than to imply that all platforms share efficacy, selectivity or clinical readiness. Keywords: polyamine metabolism, cancer nanotherapy, metabolic nanoreactor, clinical translation, enzyme nanocatalysis, tumor metabolism