Advanced cancer patients face a high risk of sepsis due to immune suppression and infection susceptibility. To tackle this challenge, we developed an innovative animal model that simulates the clinical scenario of late-stage cancer complicated by sepsis and designed a sialic acid (SA)-modified paclitaxel (PTX) liposome (PTX-SAL). This formulation specifically targets overactivated peripheral blood neutrophils (PBNs) by binding to L-selectin on their surface. It effectively eliminates hyperactive neutrophils and blocks their migration, thus reducing infiltration into tumor and inflammation sites. In sepsis and melanoma mouse models, PTX-SAL demonstrated superior therapeutic efficacy and a favorable safety profile. Notably, in the late-stage tumor model with sepsis, PTX-SAL significantly improved survival rates, with a 72-hour survival rate of 66.7%. In stark contrast, the PTX solution (PTX-S) group exhibited accelerated mortality, with all animals succumbing within 24 h, highlighting the detrimental effects of PTX-S's non-selective cytotoxicity on immune cells. These findings underscore the superior long-term safety and therapeutic advantage of nanomedicines like PTX-SAL over conventional drug formulations. In summary, SA-modified nanomedicines offer a dual benefit by targeting and eliminating inflammatory neutrophils, addressing both tumor progression and sepsis, and significantly reducing mortality in preclinical models. This innovative strategy fills a critical gap in the treatment of advanced cancer complicated by sepsis.