The presence of lymph node (LN) metastases guides cancer staging and worsens prognoses. Incomplete lymphadenectomy of metastatic LNs may end up with disease recurrence, while excessive resection can result in increased postoperative complications with even no survival benefit. Thus, effective non-invasive methods to treat metastatic LNs would be highly desirable. Here, we develop an enzyme-responsive formulation of small-sized doxorubicin-loaded mesoporous silica nanoparticles (DMSN, 40 nm) encapsulated in nanoliposomes (DMSN@Pla-Lipo, 160 nm). The liposomal membrane contains 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), two phospholipids sensitive to secreted phospholipase A2 in human colorectal tumors. In an orthotopic colorectal murine tumor model, phospholipase-induced membrane permeabilization triggers the liberation of DMSN from liposomes for enhanced tumor penetration, conferring an enhanced suppression for the primary tumor. Furthermore, through translocation into metastatic LNs via tumor lymphatics, metastatic tumor cells in LNs are eradicated. Metastases to other major organs are also suppressed, which can be ascribed to the inhibition of colorectal cancer metastasis-associated TGF-beta, Wnt, and Hippo signaling pathways in metastatic LNs. The treatment confers an 80% 90-day survival rate in this aggressive tumor model. Taken together, this study demonstrates a deliberate treatment approach for management of both primary tumors and metastatic LNs through multistage drug delivery.