We propose a novel iterative-optimization-inspired direct targeting strategy (DTS) for smart nanosystems, which harness swarms of externally manipulable nanoswimmers assembled by magnetic nanoparticles (MNPs) for knowledge-aided tumor sensitization and targeting. We aim to demonstrate through computational experiments that the proposed DTS can significantly enhance the accumulation of MNPs in the tumor site, which serve as a contrast agent in various medical imaging modalities, by using the shortest possible physiological routes and with minimal systemic exposure. The epicenter of a tumor corresponds to the global maximum of an externally measurable objective function associated with an in vivo tumor-triggered biological gradient; the domain of the objective function is the tissue region at a high risk of malignancy; swarms of externally controllable magnetic nanoswimmers for tumor sensitization are modeled as the guess inputs. The objective function may be resulted from a passive phenomenon such as reduced blood flow or increased kurtosis of microvasculature due to tumor angiogenesis; otherwise, the objective function may involve an active phenomenon such as the fibrin formed during the coagulation cascade activated by tumor-targeted “activator” nanoparticles. Subsequently, the DTS can be interpreted from the iterative optimization perspective: guess inputs (i.e., swarms of nanoswimmers) are continuously updated according to the gradient of the objective function in order to find the optimum (i.e., tumor) by moving through the domain (i.e., tissue under screening). Along this line of thought, we propose the computational model based on the gradient descent (GD) iterative method to describe the GD-inspired DTS, which takes into account the realistic in vivo propagation scenario of nanoswimmers. By means of computational experiments, we show that the GD-inspired DTS yields higher probabilities of tumor sensitization and more significant dose accumulation compared to the “brute-force” search, which corresponds to the systemic targeting scenario where drug nanoparticles attempt to target a tumor by enumerating all possible pathways in the complex vascular network. The knowledge-aided DTS has potential to enhance the tumor sensitization and targeting performance remarkably by exploiting the externally measurable, tumor-triggered biological gradients. We believe that this work motivates a novel biosensing-by-learning framework facilitated by externally manipulable, smart nanosystems.