TY  - JOUR
T1  - Co-Designing mRNA Cargo and Lipid Nanoparticles across Sequence Function, Intracellular Trafficking, Biodistribution, and Manufacturabil
A1  - Hassan Ali
A1  - Mariam Farooq
A1  - Usman Shah
A1  - Bilal Khan
A1  - Sana Malik
JF  - Pharmacophore
JO  - Pharmacophore
SN  - 2229-5402
Y1  - 2026
VL  - 17
IS  - 4
DO  - 10.51847/4YlxCn8KFc
SP  - 71
EP  - 82
N2  - Messenger RNA therapeutics depend on a coupled molecular and delivery system in which sequence design, chemical composition, particle assembly, intracellular trafficking, tissue exposure, and manufacturing conditions jointly shape performance. Yet development programs commonly optimize cargo and lipid nanoparticles in partially separated workflows, often privileging a single readout such as expression, uptake, or encapsulation. This article addresses that fragmentation by proposing an original mRNA–lipid nanoparticle co-design architecture that treats the cargo, carrier, process, biological context, and therapeutic objective as interacting design states rather than independent modules. The approach is a theory-building synthesis of recent pharmaceutical, bioengineering, and computational evidence, organized around causal uncertainty, multiobjective trade-offs, and staged validation. The central contribution is a proposed architecture in which sequence–function relationships, innate-immune effects, lipid composition, particle formation, endosomal escape, biodistribution, and manufacturability are connected through explicit intermediate states and feedback loops. The architecture distinguishes predictive ranking from experimental confirmation, particle uptake from productive cytosolic delivery, organ exposure from target-cell function, and laboratory feasibility from scalable pharmaceutical control. It further argues that no universal optimum exists across vaccination, protein replacement, gene editing, immune modulation, and ex vivo engineering because each context assigns different weights to expression kinetics, inflammatory signaling, targeting, durability, safety, and process robustness. The proposal is not an empirically validated model, regulatory framework, or operational decision tool. Its value is to provide a disciplined structure for designing experiments, integrating heterogeneous evidence, reporting uncertainty, and preventing locally optimized cargo or formulation choices from being mistaken for a therapeutically and manufacturably coherent product.
UR  - https://pharmacophorejournal.com/article/co-designing-mrna-cargo-and-lipid-nanoparticles-across-sequence-function-intracellular-trafficking-xc7xbjysul4xbag
ER  -