<p>Transdermal drug delivery systems offer advantages such as avoiding hepatic first-pass metabolism, maintaining steady plasma concentrations, and improving patient compliance. However, only a few drugs can passively diffuse and permeate the skin barriers. Microneedles have emerged as a promising platform for overcoming the skin barrier for efficient drug delivery. Charge-reversal nanoparticles are a novel drug delivery formulation that responds to stimuli, such as pH, reactive oxygen species, and enzymes, by altering their charge. Hence, charge-reversal nanoparticles can release drugs by penetrating the negatively charged cell surface. Although direct studies on charge-reversal nanoparticles within microneedle systems are scarce, their complementary features indicate their potential for future integration. This review focuses on the emerging trends and perspectives of charge-reversal nanoparticle-based microneedles. Emerging trends include stimuli-responsive microneedle designs, nanoparticles with functional modifications, and their integration with other technologies. Perspectives such as personalized medicine, vaccine delivery, immunotherapy, gene therapy, and CRISPR delivery are discussed. The objective of this review is to critically analyze recent advancements in charge-reversal nanoparticle-based microneedle systems, focusing on their mechanisms, fabrication approaches, biomedical applications, and translational perspectives. Overall, charge-reversal nanoparticle-based microneedle technology has the potential to change the way drugs are delivered. This will pave the way for innovative research in drug formulation and development.</p>