Chronic kidney disease (CKD) is a major global health concern, affecting an estimated 844 million people worldwide. A substantial number of CKD cases are attributed to genetic kidney diseases, encompassing a wide range of inherited disorders. Current treatments for many genetic kidney diseases are limited, often focusing on symptom management rather than addressing the underlying genetic defects. The lack of effective therapies highlights the urgent need for novel therapeutic approaches. Nanomedicine, with its proven success in other disease areas such as cancer and infectious diseases, offers a promising avenue for targeted drug delivery in CKD. This Perspective explores the potential of nanomedicine and other advanced therapies to improve treatment outcomes for genetic kidney diseases, focusing on the unique physiological challenges presented by the kidney and the need for innovative strategies to overcome these challenges. The paper aims to provide an overview of the current clinical status of genetic kidney diseases, delve into relevant aspects of kidney physiology, and summarize the latest advancements in nanoparticle design for renal targeting. Finally, it identifies critical knowledge gaps and proposes a call to action emphasizing the importance of collaborative efforts to translate nanomedicine research into clinically relevant therapies for patients with genetic kidney diseases.

The paper reviews existing literature on genetic kidney diseases, focusing on their clinical presentation, genetic causes, and current treatment limitations. It also examines the existing body of research on nanoparticle design for kidney targeting, highlighting the influence of particle size, charge, and shape on renal accumulation and filtration. The authors explore both passive and active targeting strategies, including the use of peptide ligands, antibodies, and aptamers. The review also considers the challenges of delivering therapies to the developing fetal kidney and the use of various delivery methods including intra-amniotic injection and vitelline vein injection. Finally, the paper discusses the use of cell therapies such as stem cell therapy and renal autologous cell therapy in treating genetic kidney diseases. The literature review supports the need for new therapeutic strategies due to the limitations of existing treatments and the lack of effective therapies for many genetic kidney diseases.

This Perspective uses a narrative review methodology. It synthesizes information from existing research articles, clinical trial data, and regulatory guidelines to provide a comprehensive overview of the topic. The authors systematically collect and analyze information from peer-reviewed publications, focusing on studies related to the clinical landscape of genetic kidney diseases, kidney physiology, nanoparticle design for kidney targeting, emerging technological strategies, and existing challenges in the field. The selection of papers is based on their relevance to the scope of the Perspective and includes a range of study designs, such as preclinical and clinical studies, in vitro and in vivo experiments, and reviews of the literature. The authors carefully evaluate the information presented, highlighting areas of agreement and disagreement within the literature. The information gathered is used to support claims made within the text and to draw conclusions about the current state of the field and future directions for research and development. The data synthesis process involved a critical appraisal of the strengths and limitations of various studies to ensure the robustness and reliability of the information presented.

The Perspective emphasizes the significant unmet need for effective therapies for genetic kidney diseases. It highlights that while nanomedicine has shown great promise in treating other diseases, its application in treating genetic kidney diseases is still in its infancy. The authors detail the complex physiology of the kidney, emphasizing the glomerular filtration barrier (GFB) as a key obstacle to drug delivery. They find that nanoparticle physicochemical properties, particularly size and charge, play critical roles in determining kidney accumulation and filtration. Particles smaller than 10 nm generally cross the GFB most efficiently, although ultrasmall nanoparticles (<1 nm) may be retained by the glycocalyx. Surface charge also influences filtration, with cationic particles showing increased kidney retention compared to anionic particles. Nanoparticle shape also plays a role, with non-spherical particles exhibiting longer circulation half-times. Alternative strategies to bypass the GFB, such as targeting mesangial cells through phagocytosis or proximal tubule cells through transcytosis, are also discussed. Active targeting strategies, using peptide ligands, antibodies, and aptamers, can enhance the specificity of drug delivery to target kidney cells. The challenges of treating congenital kidney diseases are underscored, along with potential strategies like gene/protein fetal delivery via the vitelline vein or intraamniotic injection. The perspective reviews the promise of cell-based therapies, including stem cell therapy and renal autologous cell therapy, in treating these diseases, but acknowledges the limited clinical translation of these approaches. The authors conclude that addressing the knowledge gaps in both genetic kidney diseases and kidney nanomedicine is crucial for advancing effective therapies and requires collaborative efforts involving basic scientists, clinicians, industry, and regulatory bodies.

The findings of this Perspective highlight the urgent need for innovation in the treatment of genetic kidney diseases. The current limitations of existing therapies, coupled with the complexity of kidney physiology, necessitate the development of targeted drug delivery systems. Nanomedicine offers a promising approach, but challenges remain in optimizing nanoparticle design to achieve effective kidney targeting while minimizing off-target effects and toxicity. The discussion emphasizes the need for a more thorough understanding of nanoparticle-kidney interactions, including the role of the protein corona, to guide the design of more effective nanocarriers. The significant unmet need in treating congenital kidney diseases, particularly those affecting fetuses and infants, underscores the importance of developing safe and effective strategies for in utero delivery of therapeutic agents. The success of nucleic acid-based nanomedicine in other disease areas suggests potential for application in genetic kidney diseases, but translational research is needed to overcome the current challenges in clinical development. The integration of organoid models and advanced technologies like machine learning can significantly accelerate the discovery and development of new therapies.

This Perspective underscores the critical need for innovative drug delivery strategies to address the significant unmet clinical need in genetic kidney diseases. Nanomedicine holds immense promise, but successful translation to the clinic requires overcoming challenges related to kidney physiology, optimizing nanoparticle design, and improving our understanding of disease mechanisms. Collaborative efforts, integrating expertise from diverse fields and involving all stakeholders, are essential to accelerate the development of effective and safe therapies for this patient population. Future research should focus on improving our understanding of nanoparticle-kidney interactions, developing more targeted delivery systems, and translating promising preclinical findings into clinical trials.

As a perspective article, this review is limited by its reliance on existing literature. The authors' interpretations and conclusions are based on the currently available data, which may evolve as new research is conducted. The focus is primarily on monogenic kidney diseases, and the extent to which the findings are generalizable to other forms of CKD may be limited. Additionally, the review focuses heavily on nanomedicine approaches, and other potential therapeutic avenues, such as gene therapy, are not explored in great depth.