Nanoparticles and Medicine Thirty Years After the First FDA Approval: Time to Renew the Vows

Thirty years after the approval of Doxil, nanomedicine has generated extraordinary scientific output and enabled therapeutic modalities that would otherwise have remained impractical. Its clinical translation, however, remains more limited than the scale and sophistication of the field might suggest, particularly when targeted systemic delivery is required. In the recent past, others have highlighted those limitations, however, what concerns us is that some of the assumptions that constrained earlier generations of nanomedicines are now re-emerging in AAV-based gene therapy and in vivo CAR-T platforms. More precise payloads do not make delivery more precise, nor do viral vectors escape the biological barriers encountered by synthetic nanoparticles. In this Perspective, we revisit the liver paradox, the distinction between organ accumulation and functional delivery, the protein corona and the promise of biomimetic systems. Our intention is not to add another catalogue of limitations, but to ask what should change. We argue that the next phase of drug delivery should be less focused on adding complexity to the carrier and more committed to quantifying its biological journey.