Stimuli-responsive nanocarriers for targeted mRNA therapeutics: a paradigm shift in mRNA delivery for biomedical...

Messenger RNA (mRNA) based therapeutics have emerged as a transformative modality with immense potential for treating infectious diseases, cancer, genetic disorders, and other complex conditions. Despite their promise, clinical translation has been challenged by mRNA's intrinsic instability, rapid degradation, and limited target specificity. The therapeutic value of mRNA lies in its ability to precisely modulate or restore protein expression, offering a versatile platform for personalized medicine. While conventional delivery approaches have yielded modest improvements, the integration of nanotechnology, particularly stimuli-responsive, nanoparticle-mediated systems, represents a breakthrough in overcoming these limitations. These advanced nanocarriers respond to both endogenous physiological triggers (such as pH shifts, redox gradients, reactive oxygen species, enzymatic activity, and hypoxic environments) and exogenous stimuli (including light, ultrasound, magnetic fields, and temperature changes), thereby enabling controlled, site-specific, and temporally regulated mRNA release. This dual responsiveness enhances therapeutic efficacy by improving mRNA stability, bioavailability, and minimizing off-target immune activation. This review highlights the design principles, mechanisms, and therapeutic applications of stimuli-responsive nanocarriers in mRNA delivery. It underscores recent innovations in nanoparticle engineering that address existing challenges and pave the way for next-generation precision medicine. Together, these advancements signal a paradigm shift in targeted mRNA therapy, offering new hope for treating previously intractable diseases.