In a mixture of colloidal particles and polymer molecules,the particles may experience an attractive“depletion force”if the size of the polymer molecule is larger than the interparticle separation.This is because individual polymer molecules experience less conformational entropy if they stay between the particles than they escape the inter-particle space, which results in an osmotic pressure imbalance inside and outside the gap and leads to interparticle attraction.This depletion force has been the subject of several studies since the 1980s,but the direct measurement of this force is still experimentally challenging as it requires the detection of energy variations of the order of k_BT and beyond.We present here our results for applying total internal reflection microscopy(TIRM) to directly measure the interaction between a free-moving particle and a flat surface in solutions consisting of small water-soluble organic molecules or polymeric surfactants.Our results indicate that stable nanobubbles(ca.150 nm) exist free in the above aqueous solutions.More importantly,the existence of such nanobubbles induces an attraction between the spherical particle and flat surface.Using TIRM,we are able to directly measure such weak interaction with a range up to 100 nm.Furthermore,we demonstrate that by employing thermo-sensitive microgel particles as a depleting agent,we are able to quantitatively measure and reversibly control k_BYT-scale depletion attraction as function of solution pH. In a mixture of colloidal particles and polymer molecules, the particles may experience an attractive “depletion force ” if the size of the polymer molecule is larger than the interparticle separation. This is because individual polymer molecules experience less conformational entropy if they stay between the particles than they escape the inter-particle space, which results in an osmotic pressure imbalance inside and outside the gap and leads to interparticle attraction. This depletion force has been the subject of several studies since the 1980s, but the direct measurement of this force is still experimentally challenging as it requires the detection of energy variations of the order of k_BT and beyond. We present here our results for applying total internal reflection microscopy (TIRM) to directly measure the interaction between a free-moving particle and a flat surface in solutions consisting of small water-soluble organic molecules or polymeric surfactants. Our results indicate that stabl e nanobubbles (ca.150 nm) exist free in the above aqueous solutions. Importantly, the existence of such nanobubbles induces an attraction between the spherical particle and flat surface. Using TIRM, we are able to directly measure such weak interaction with a range up to 100 nm. Fermentmore, we demonstrate that by employing thermo-sensitive microgel particles as a depleting agent, we are able to quantitatively measure and reversibly control k_BYT-scale depletion attraction as function of solution pH.