We have developed a macromolecular prodrug platform based on poly (L-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in a SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. or i.d. administration, based on immunohistochemical analysis with high-resolution microscopy. As a proof-of-concept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and non-enzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood Supporting Information The Supporting Information is available free of charge via the Internet at http://pubs.acs.org SEC chromatograms of PLS-488 and PLS-Cy7.5; 1 H NMR spectra of PLS, partially capped PLS, fully capped PLS, FTC, 2-(2methoxyethoxy)ethanamine, and FTC; binding and uptake of PLS-488 in RAW 264.7 cells following co-treatment with partially capped PLS, fully capped PLS, poly C, or poly I; flow cytometry plots of RAW 264.7 and clone 1/2 cells following 24 h incubation with PLS-488; confocal images of PLS-488 uptake in RAW 264.7 and clone ½ cells; whole-body images of PLS-Cy7.5 treated mice; ex vivo images of organs harvested 6 h after PLS-Cy7.5 i.v. injection; IHC staining controls; standard curves of FTC with and without NaOH hydrolysis.