Smart Colloidal Systems as Drug Delivery and Therapeutic Modulation Platforms for Renal Cell Carcinoma

Liming Sun,1,* Xinming Zhao,1,* Xiaoting Li,2,* Zhanmeng Zhu,1 Guangzhen Wu11Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China; 2Department of Radiology, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangzhen Wu, Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China, Email wuguang0613@hotmail.com Zhanmeng Zhu, Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China, Email zhuzhanmeng@firsthosp-dmu.comAbstract: Renal cell carcinoma (RCC) is one of the major malignant tumors of the genitourinary system and remains difficult to treat in advanced or recurrent settings. Although surgery, antiangiogenic targeted therapy, immune checkpoint blockade, mTOR inhibition, and HIF-2α-targeted therapy have improved clinical outcomes, recurrence, therapeutic resistance, heterogeneous tumor exposure, and systemic toxicity continue to restrict long-term efficacy. Smart colloidal systems have attracted attention as drug delivery and therapeutic modulation platforms because their size, surface properties, composition, and responsiveness can be engineered to improve drug stability, tumor accumulation, intracellular delivery, and controlled release. In this review, "smart colloidal systems” refers to functionally engineered colloidal platforms whose design confers therapeutic behavior beyond passive drug encapsulation, including selective tumor- or cell-directed delivery, controlled or stimulus-triggered release or activation, enhanced intracellular delivery, intrinsic carrier-mediated biological effects, and coordinated multimodal therapy. In RCC, these systems have been explored for the delivery of tyrosine kinase inhibitors, immune agonists, checkpoint-regulating nucleic acids, therapeutic genes, siRNAs, ferroptosis-inducing agents, photosensitizers, sonosensitizers, and combination regimens. This review summarizes recent progress in smart colloidal systems for RCC therapy from a treatment-modality perspective, including targeted therapy, immunotherapy, gene and RNA therapy, metabolic and ferroptosis-based therapy, externally triggered therapy, and combination treatment. However, most RCC-directed smart colloidal systems remain at the preclinical stage. Toxicity, renal safety, immune compatibility, biodistribution, manufacturing feasibility, and clinical translation are also discussed. By linking the delivered cargo, colloidal platform, biological rationale, and antitumor strategy, this review aims to clarify the potential value and limitations of smart colloidal systems in RCC treatment.Keywords: clear cell renal cell carcinoma, smart colloidal systems, nanoparticles, drug delivery, immunotherapy, RNA therapy