<p>Genipin-crosslinked nanocarrier systems demonstrate enhanced physicochemical and therapeutic performance across multiple platforms, including nanoparticles, liposomes, hydrogels, nanogels, and lipid-based systems. These systems consistently achieve 25–35% amine crosslinking efficiency, resulting in improved structural stability, higher drug encapsulation efficiency, and sustained release profiles compared with non-crosslinked or synthetically crosslinked counterparts. Preclinical evidence indicates that approximately 25–35% of reported studies include in vivo validation, demonstrating prolonged systemic circulation, enhanced tumor accumulation, significant tumor growth inhibition, and reduced off-target toxicity. Mechanistically, genipin induces mitochondrial dysfunction via UCP2 inhibition, leading to elevated intracellular ROS levels, modulation of Bax/Bcl-2 balance, activation of caspase cascades, and suppression of NF-κB, PI3K/Akt/mTOR, and STAT3 signaling pathways. These effects collectively promote apoptosis, ferroptosis, anti-angiogenesis, and inhibition of metastasis. Integration of genipin into nanocarriers improves pharmacokinetic parameters, including increased half-life, enhanced bioavailability, and reduced systemic clearance, while enabling synergistic therapeutic strategies such as chemo-, gene-, and phototherapy. Compared with conventional crosslinkers, genipin exhibits markedly lower cytotoxicity and superior biocompatibility, supporting higher cell viability and reduced inflammatory responses. However, challenges remain, including slower crosslinking kinetics, formulation variability, scalability limitations, and insufficient long-term in vivo safety data. Overall, genipin-based nanocarriers demonstrate significant potential as multifunctional platforms for improving the efficacy and safety of cancer therapy, though further translational and clinical validation is required.</p>