DXd (Exatecan derivative), a novel TOPO-I inhibitor, exhibits high membrane permeability and an efficient bystander effect, serving as a critical cytotoxic drug component in antibody-drug conjugates (ADCs). However, its poor stability, high toxicity and non-ionizable structure limit its clinical applications. Basic/acid/metal coordination modifying strategy offers a potential solution to remotely load non-ionizable drugs into liposomes. However, achieving an optimal balance between therapeutic efficacy and safety remains a major challenge. In this study, DXd was used as a model compound to design and synthesize a series of weakly basic derivatives (DXdd), incorporating various basic moieties linked via alkyl chains of different lengths. The alkyl chain length significantly influenced both the chemical stability and antitumor activity of DXdd. Among them, DXdd with four alkyl chains (DXdd-4PA) demonstrated potent antitumor efficacy with minimal acute and cumulative toxicity. Subsequent optimization of the liposome size loaded with DXdd-4PA revealed that 80 nm was optimal for cancer therapy. Overall, this work provides a valuable framework for the rational design of non-ionizable drugs suitable for remote loading into liposomes, and enhances the translational potential of DXd-based therapeutics.