New research from the University of Copenhagen suggests that internal disorder within lipid nanoparticles (LNPs) improves intracellular release of RNA cargo. Using a high-throughput, single-particle analysis able to measure millions of nanoparticles individually, investigators identified two subpopulations: highly organized particles that retain cargo and amorphous particles that release cargo more effectively inside cells. The findings, reported at the Biophysical Society meeting, challenge the prevailing industry focus on maximizing payload packing efficiency and suggest formulation strategies that favor partial internal disorder to enhance therapeutic payload bioavailability. Artu Breuer and colleagues warned that overly tight lipid-RNA interactions can impede release in endosomal environments. The work could shift LNP design for mRNA vaccines and therapeutics across oncology and rare diseases, prompting developers to balance encapsulation efficiency with release kinetics to improve clinical potency.