The biological memory buffer hypothesis: can programmable nanocarriers shape cellular memory to improve the durability of mRNA vaccines and gene therapies?

Introduction: Messenger RNA vaccines and gene therapies enable rapid and programmable biological intervention, but their therapeutic durability remains variable. Existing nanomedicine research primarily evaluates delivery efficiency, targeting, RNA protection and early protein expression, which do not fully explain why some biological effects persist while others rapidly decline. Methods: This Hypothesis and Theory article presents a narrative conceptual synthesis of peer-reviewed literature on lipid nanoparticle delivery, mRNA vaccinology, RNA therapeutics, genome editing, trained innate immunity, epigenetic regulation and regenerative medicine. Evidence was integrated to develop an operational and falsifiable framework for evaluating the contribution of nanocarriers to therapeutic durability. Results: We propose the Biological Memory Buffer Hypothesis, according to which programmable nanocarriers may influence biological systems that encode, maintain or recall therapeutic information after RNA delivery. The framework distinguishes payload persistence from biological-outcome persistence and introduces three measurable constructs: therapeutic memory engineering, nanocarrier memory capacity and the therapeutic persistence window. It further proposes matched-cargo and matched-early-exposure experiments, candidate monophasic and biphasic decay models, a minimum durability reporting set and safety monitoring for maladaptive innate immune imprinting. Discussion: The framework does not assume that adaptive immune memory, trained immunity, epigenetic regulation and regenerative repair share a single molecular mechanism. Rather, it treats them as distinct biological substrates with a common functional relevance to durability. The hypothesis is falsifiable: failure to detect reproducible carrier-attributable differences under matched conditions would argue against nanocarrier memory capacity as an independent determinant. Incorporating longitudinal, tissue-specific and host-stratified durability measurements may support the rational development of longer-lasting RNA vaccines and gene therapies.