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PLGA nanotherapeutics though representing a most promising platform for targeted cancer therapy are confronted with low stability and insufficient tumor cell uptake. Here, we report that hyaluronic acid (HA) coated PLGA nanoparticulate docetaxel (DTX-HPLGA) is particularly robust and can effectively target and suppress orthotopic human lung cancer. DTX-HPLGA was easily prepared with a small size of 154 nm and negative surface charge of −22.7 mV by nanoprecipitation and covalent coating with HA. DTX-HPLGA displayed a low IC50 of 0.91 μg/mL in CD44+ A549 cells and a prolonged elimination half-life of 4.13 h in nude mice. Interestingly, DTX-HPLGA demonstrated 4.4-fold higher accumulation in the cancerous lung than free DTX, reaching a remarkable level of 13.7 %ID/g at 8 h post-injection, in orthotopic human A549 lung cancer-bearing mice. Accordingly, DTX-HPLGA exhibited significantly better inhibition of tumor growth than free DTX, leading to healthy mice growth and markedly improved survival time. DTX-HPLGA with easy fabrication, excellent stability and tumor accumulation, effective tumor suppression, and low side effects is of particular interest for targeted chemotherapy of lung cancers.Hyaluronic acid coating endows PLGA nanoparticulate docetaxel enhanced stability and superior tumor cell selectivity, leading to long circulation time, high drug accumulation in the cancerous lung, effective tumor inhibition and reduced systemic toxicity.